id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
08b386773b66d3df7c79ee8f4e7a60e833c18a39 | wikidoc | P2RY8 | P2RY8
P2Y purinoceptor 8 is a protein that in humans is encoded by the P2RY8 gene.
# Function
The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene is moderately expressed in undifferentiated HL60 cells, and is located on both chromosomes X and Y.
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma. | P2RY8
P2Y purinoceptor 8 is a protein that in humans is encoded by the P2RY8 gene.[1][2]
# Function
The protein encoded by this gene belongs to the family of G-protein coupled receptors, that are preferentially activated by adenosine and uridine nucleotides. This gene is moderately expressed in undifferentiated HL60 cells, and is located on both chromosomes X and Y.[2]
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.[3] | https://www.wikidoc.org/index.php/P2RY8 | |
a623e96bf5a1ce62e42b114117650db76bebdb56 | wikidoc | PA2G4 | PA2G4
Proliferation-associated protein 2G4 (PA2G4) also known as ErbB3-binding protein 1 (EBP1) is a protein that in humans is encoded by the PA2G4 gene.
# Function
This gene encodes an RNA-binding protein that is involved in growth regulation. This protein is present in pre-ribosomal ribonucleoprotein complexes and may be involved in ribosome assembly and the regulation of intermediate and late steps of rRNA processing. This protein can interact with the cytoplasmic domain of the ErbB3 receptor and may contribute to transducing growth regulatory signals. This protein is also a transcriptional corepressor of androgen receptor-regulated genes and other cell cycle regulatory genes through its interactions with histone deacetylases. This protein has been implicated in growth inhibition and the induction of differentiation of human cancer cells. Paradoxically, the expression of EBP1 is decreased in prostate cancer , but increased in Acute Myelogneous Leukemia. Six pseudogenes, located on chromosomes 3, 6, 9, 18, 20 and X, have been identified.
# Interactions
PA2G4 has been shown to interact with ERBB3, retinoblastoma protein, and androgen receptor. | PA2G4
Proliferation-associated protein 2G4 (PA2G4) also known as ErbB3-binding protein 1 (EBP1) is a protein that in humans is encoded by the PA2G4 gene.[1]
# Function
This gene encodes an RNA-binding protein that is involved in growth regulation. This protein is present in pre-ribosomal ribonucleoprotein complexes and may be involved in ribosome assembly and the regulation of intermediate and late steps of rRNA processing. This protein can interact with the cytoplasmic domain of the ErbB3 receptor and may contribute to transducing growth regulatory signals. This protein is also a transcriptional corepressor of androgen receptor-regulated genes and other cell cycle regulatory genes through its interactions with histone deacetylases. This protein has been implicated in growth inhibition and the induction of differentiation of human cancer cells. Paradoxically, the expression of EBP1 is decreased in prostate cancer [2], but increased in Acute Myelogneous Leukemia.[3] Six pseudogenes, located on chromosomes 3, 6, 9, 18, 20 and X, have been identified.[4]
# Interactions
PA2G4 has been shown to interact with ERBB3,[5][6] retinoblastoma protein,[7] and androgen receptor.[8] | https://www.wikidoc.org/index.php/PA2G4 | |
6572f9588a911f98050ff274537951961ea1e642 | wikidoc | PAC-1 | PAC-1
# Overview
PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 has shown good results in mouse models and is being further evaluated for use in humans.
# Function and discovery
PAC-1 (pronounced "pack one") was discovered at the University of Illinois at Urbana-Champaign during a process that screened many chemicals for anti-tumor potential. This molecule, when delivered to cancer cells, signals the cells to self-destruct by activating an "executioner" protein, procaspase-3. Then, the activated executioner protein begins a cascade of events that destroys the machinery of the cell.
# Uses of apoptosis in the body and its irregularities
This cascade of events is named apoptosis. Apoptosis is self-induced in cells to combat infections or DNA damage. For instance, when a cell in one's body is infected with a bacterium or virus, it will self-destruct to take away the resources needed by the virus to proliferate. Apoptosis is also found to help in embryo development (destroying the webbing in between an embryo's fingers to separate the fingers) and the regular replenishment of cells that are constantly being used up or destroyed (cells that line the intestinal tract), also called homeostasis.
The problem lies when one part of the apoptosis pathway is broken. Normally, the balance between cell division and apoptosis is rigorously regulated to keep the integrity of organs and tissues. Examples of broken apoptosis pathways occur in many cancers. If old lung cells cannot self-destruct to make room for new lung cells, a large mass of cells form and a tumor is made.
In many cases, the apoptotic pathway is disrupted because procaspase-3, the executioner protein, cannot be activated by the cell. This is analogous to an executioner who does not have orders to kill. Without the orders, the condemned will not die. The same analogy can be made with procaspase-3. Without activated procaspase-3, the apoptotic cascade will not occur and the cell will not destroy itself no matter how necessary it may be. PAC-1 acts a replacement order that works and bypasses the lawyers, court orders, and governor's calls. It will activate procaspase-3 indiscriminately.
# How PAC-1 affects the apoptotic process
In cells, the executioner protein, caspase-3, is stored in its inactive form, procaspase-3. This way, the cell can quickly undergo apoptosis by activating the protein that is already there. This inactive form is called a zymogen. Procaspase-3 has a “safety catch” made of three aspartate amino acids. When this safety catch is released by the cell, procaspase-3 is activated to caspase-3, which starts the apoptotic cycle. PAC-1 cleaves these three amino acids to activate procaspase-3 into caspase-3. Also, caspase-3 further activates other molecules of procaspase-3 in the cell, causing an exponential increase in caspase-3 concentration. PAC-1 facilitates this process and causes the cell to undergo apoptosis quickly.
Unfortunately, a selectivity problem arises because procaspase-3 is present in most cells of the body. However, it has been shown that in many cancers, including certain neuroblastomas, lymphomas, leukemias, melanomas, and liver cancers, procaspase-3 is present in higher concentrations. For instance, lung cancer cells can have over 1000 times more procaspase-3 than normal cells. Therefore, by controlling the dosage, one can achieve selectivity between normal and cancerous cells.
# Further research and human application
Thus far, PAC-1 seems promising as a new anti-tumor drug. It is synthetically available and a few mouse trials have been performed with moderate success. PAC-1 is the first of many small molecules to directly influence the apoptotic machinery of cells. | PAC-1
# Overview
PAC-1 (first procaspase activating compound) is a synthesized chemical compound that selectively induces apoptosis, or cell suicide, in cancerous cells. PAC-1 has shown good results in mouse models and is being further evaluated for use in humans.
# Function and discovery
PAC-1 (pronounced "pack one") was discovered at the University of Illinois at Urbana-Champaign during a process that screened many chemicals for anti-tumor potential. This molecule, when delivered to cancer cells, signals the cells to self-destruct by activating an "executioner" protein, procaspase-3. Then, the activated executioner protein begins a cascade of events that destroys the machinery of the cell.
# Uses of apoptosis in the body and its irregularities
This cascade of events is named apoptosis. Apoptosis is self-induced in cells to combat infections or DNA damage. For instance, when a cell in one's body is infected with a bacterium or virus, it will self-destruct to take away the resources needed by the virus to proliferate. Apoptosis is also found to help in embryo development (destroying the webbing in between an embryo's fingers to separate the fingers) and the regular replenishment of cells that are constantly being used up or destroyed (cells that line the intestinal tract), also called homeostasis.
The problem lies when one part of the apoptosis pathway is broken. Normally, the balance between cell division and apoptosis is rigorously regulated to keep the integrity of organs and tissues. Examples of broken apoptosis pathways occur in many cancers. If old lung cells cannot self-destruct to make room for new lung cells, a large mass of cells form and a tumor is made.
In many cases, the apoptotic pathway is disrupted because procaspase-3, the executioner protein, cannot be activated by the cell. This is analogous to an executioner who does not have orders to kill. Without the orders, the condemned will not die. The same analogy can be made with procaspase-3. Without activated procaspase-3, the apoptotic cascade will not occur and the cell will not destroy itself no matter how necessary it may be. PAC-1 acts a replacement order that works and bypasses the lawyers, court orders, and governor's calls. It will activate procaspase-3 indiscriminately.
# How PAC-1 affects the apoptotic process
In cells, the executioner protein, caspase-3, is stored in its inactive form, procaspase-3. This way, the cell can quickly undergo apoptosis by activating the protein that is already there. This inactive form is called a zymogen. Procaspase-3 has a “safety catch” made of three aspartate amino acids. When this safety catch is released by the cell, procaspase-3 is activated to caspase-3, which starts the apoptotic cycle. PAC-1 cleaves these three amino acids to activate procaspase-3 into caspase-3. Also, caspase-3 further activates other molecules of procaspase-3 in the cell, causing an exponential increase in caspase-3 concentration. PAC-1 facilitates this process and causes the cell to undergo apoptosis quickly.[1]
Unfortunately, a selectivity problem arises because procaspase-3 is present in most cells of the body. However, it has been shown that in many cancers, including certain neuroblastomas, lymphomas, leukemias, melanomas, and liver cancers, procaspase-3 is present in higher concentrations.[1] For instance, lung cancer cells can have over 1000 times more procaspase-3 than normal cells.[1] Therefore, by controlling the dosage, one can achieve selectivity between normal and cancerous cells.
# Further research and human application
Thus far, PAC-1 seems promising as a new anti-tumor drug. It is synthetically available and a few mouse trials have been performed with moderate success. PAC-1 is the first of many small molecules to directly influence the apoptotic machinery of cells. | https://www.wikidoc.org/index.php/PAC-1 | |
a9d493effd62b96fa9db9b03b433861b581ffab5 | wikidoc | PACS1 | PACS1
Phosphofurin acidic cluster sorting protein 1, also known as PACS-1, is a protein that in humans is encoded by the PACS1 gene.
# Function
The PACS-1 protein has a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance.
# Interactions
PACS1 has been shown to interact with Furin.
# Clinical significance
A de novo mutation c.607C>T in the PACS1 gene has been shown to result in a syndromic phenotype (colloquially called PACS1 Syndrome) that is characterized by global developmental delay, intellectual disability, and specific facial features.
## Prevalence and diagnosis
The first two cases were identified in early 2011 by doctors in the Netherlands. As of late 2014, there were 20 cases identified worldwide.
Diagnosis is typically done using full genome or exome sequencing. There are likely several more cases that will eventually be reported as knowledge of the mutation spreads and testing becomes more accessible.
## Observed and reported traits
Individuals with the mutation have been reported to have similar facial features, such as:
- Widely spaced eyes and low-set ears
- Down-slanting eye corners and mild uni-brow
- Highly arched eyebrows and long eyelashes
- Rounded “button” nose with a flat bridge
- Wide mouth with down-turned corners
- Thin upper lip and widely spaced teeth
Other common traits reported by care givers of affected individuals are:
- Low muscle tone
- Seizures
- Repetitive self-stimulatory behavior
- Sensory processing disorder
- Delayed development of gross motor skills and fine motor skills
- Delayed cognitive development
- Chewing and swallowing difficulties
- Digestion or bowel problems
- Slow growth resulting in below average height and weight
## Prognosis and treatment
In combination, these traits affect walking, talking, feeding, and learning skills. No impact on life expectancy has been found. As with many developmental disabilities, there is no "cure".
In order to improve quality of life and enhance life skills of affected individuals, care givers have found a number of tools and strategies. It is important to note that all of these may not be applicable to a particular individual, and reported effectiveness has varied. It is recommended to consult with a physician prior to initiating any form of treatment.
- physiotherapy (PT)
- occupational therapy (OT)
- speech therapy (including augmentative and alternative communication) (SPT)
- behavioural therapy (applied behavior analysis/intensive behavioural intervention etc.)
- discrete trial teaching
- early intervention programs
- massage therapy and pediatric massage
- feeding therapy
- music therapy
- hippotherapy
- hydrotherapy | PACS1
Phosphofurin acidic cluster sorting protein 1, also known as PACS-1, is a protein that in humans is encoded by the PACS1 gene.[1][2][3]
# Function
The PACS-1 protein has a putative role in the localization of trans-Golgi network (TGN) membrane proteins. Mouse and rat homologs have been identified and studies of the homologous rat protein indicate a role in directing TGN localization of furin by binding to the protease's phosphorylated cytosolic domain. In addition, the human protein plays a role in HIV-1 Nef-mediated downregulation of cell surface MHC-I molecules to the TGN, thereby enabling HIV-1 to escape immune surveillance.[3]
# Interactions
PACS1 has been shown to interact with Furin.[4]
# Clinical significance
A de novo mutation c.607C>T in the PACS1 gene has been shown to result in a syndromic phenotype (colloquially called PACS1 Syndrome) that is characterized by global developmental delay, intellectual disability, and specific facial features.[5][6]
## Prevalence and diagnosis
The first two cases were identified in early 2011 by doctors in the Netherlands.[5] As of late 2014, there were 20 cases identified worldwide.[7]
Diagnosis is typically done using full genome or exome sequencing.[8] There are likely several more cases that will eventually be reported as knowledge of the mutation spreads and testing becomes more accessible.
## Observed and reported traits
Individuals with the mutation have been reported to have similar facial features, such as:
- Widely spaced eyes and low-set ears
- Down-slanting eye corners and mild uni-brow
- Highly arched eyebrows and long eyelashes
- Rounded “button” nose with a flat bridge
- Wide mouth with down-turned corners
- Thin upper lip and widely spaced teeth
Other common traits reported by care givers of affected individuals are:
- Low muscle tone
- Seizures
- Repetitive self-stimulatory behavior
- Sensory processing disorder
- Delayed development of gross motor skills and fine motor skills
- Delayed cognitive development
- Chewing and swallowing difficulties
- Digestion or bowel problems
- Slow growth resulting in below average height and weight
## Prognosis and treatment
In combination, these traits affect walking, talking, feeding, and learning skills. No impact on life expectancy has been found. As with many developmental disabilities, there is no "cure".
In order to improve quality of life and enhance life skills of affected individuals, care givers have found a number of tools and strategies. It is important to note that all of these may not be applicable to a particular individual, and reported effectiveness has varied. It is recommended to consult with a physician prior to initiating any form of treatment.[9]
- physiotherapy (PT)
- occupational therapy (OT)
- speech therapy (including augmentative and alternative communication) (SPT)
- behavioural therapy (applied behavior analysis/intensive behavioural intervention etc.)
- discrete trial teaching
- early intervention programs
- massage therapy and pediatric massage
- feeding therapy
- music therapy
- hippotherapy
- hydrotherapy | https://www.wikidoc.org/index.php/PACS1 | |
f560899d86b3f4cbe251b248ee3d75cb4534e076 | wikidoc | PADI2 | PADI2
Protein-arginine deiminase type-2 is an enzyme that in humans is encoded by the PADI2 gene.
This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type II enzyme is the most widely expressed family member. Known substrates for this enzyme include myelin basic protein in the central nervous system and vimentin in skeletal muscle and macrophages.
This enzyme is thought to play a role in the onset and progression of neurodegenerative human disorders, including Alzheimer disease and multiple sclerosis, and it has also been implicated in glaucoma pathogenesis. This gene exists in a cluster with four other paralogous genes. | PADI2
Protein-arginine deiminase type-2 is an enzyme that in humans is encoded by the PADI2 gene.[1][2]
This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. The type II enzyme is the most widely expressed family member. Known substrates for this enzyme include myelin basic protein in the central nervous system and vimentin in skeletal muscle and macrophages.
This enzyme is thought to play a role in the onset and progression of neurodegenerative human disorders, including Alzheimer disease and multiple sclerosis, and it has also been implicated in glaucoma pathogenesis. This gene exists in a cluster with four other paralogous genes.[2] | https://www.wikidoc.org/index.php/PADI2 | |
66e92febccdfd829f696cfd4584fcd2c1e0c8d2d | wikidoc | PADI4 | PADI4
Peptidyl arginine deiminase, type IV, also known as PADI4, is a human protein which in humans is encoded by the PADI4 gene.
# Molecular biology
The human gene is found on the short arm of Chromosome 1 near the telomere (1p36.13). It is located on the Watson (plus) strand and is 55,806 bases long. The protein is 663 amino acids long with a molecular weight of 74,095 Da.
# Function
This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response. PADI4 plays a role in the epigenetics, the deimination of arginines on histones 3 and 4 can act antagonistically to arginine methylation (Chromatin modifications and their function, Kouzarides 2007, Cell, review)
The protein may be found in oligomers and binds 5 calcium ions per subunit. It catalyses the reaction:
- Protein L-arginine + H2O = protein L-citrulline + NH3
# Subcellular and tissue distribution
It is normally found in the cytoplasm, nucleus and in cytoplasmic granules of eosinophils and neutrophils. It is not expressed in peripheral monocytes or lymphocytes. It is also expressed in rheumatoid arthritis synovial tissues. | PADI4
Peptidyl arginine deiminase, type IV, also known as PADI4, is a human protein which in humans is encoded by the PADI4 gene.[1][2]
# Molecular biology
The human gene is found on the short arm of Chromosome 1 near the telomere (1p36.13). It is located on the Watson (plus) strand and is 55,806 bases long. The protein is 663 amino acids long with a molecular weight of 74,095 Da.[1]
# Function
This gene is a member of a gene family which encodes enzymes responsible for the conversion of arginine to citrulline residues. This gene may play a role in granulocyte and macrophage development leading to inflammation and immune response.[2] PADI4 plays a role in the epigenetics, the deimination of arginines on histones 3 and 4 can act antagonistically to arginine methylation (Chromatin modifications and their function, Kouzarides 2007, Cell, review)
The protein may be found in oligomers and binds 5 calcium ions per subunit. It catalyses the reaction:
- Protein L-arginine + H2O = protein L-citrulline + NH3
# Subcellular and tissue distribution
It is normally found in the cytoplasm, nucleus and in cytoplasmic granules of eosinophils and neutrophils. It is not expressed in peripheral monocytes or lymphocytes. It is also expressed in rheumatoid arthritis synovial tissues. | https://www.wikidoc.org/index.php/PADI4 | |
27e69118e2f53b649a999fdc0b444f970ab15f21 | wikidoc | PALB2 | PALB2
Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.
# Function
This gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion, a vital step of homologous recombination, (see Figure "Homologous recombinational repair of DNA double-strand damage"). PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.
# Clinical significance
Variants in the PALB2 gene are associated with an increased risk of developing breast cancer of magnitude similar to that associated with BRCA2 mutations and PALB2-deficient cells are sensitive to PARP inhibitors.
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer by scientists at the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. This has paved for the way for developing a new gene test for families where pancreatic cancer occurs in multiple family members. Tests for PALB2 have been developed by Ambry Genetics and Myriad Genetics that are now available. The PALB2 Interest Group (PALB2.org) is an international consortium of scientists and clinicians who coordinate research into this gene. They are keen to hear from women and men with PALB2 mutations.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.
# Meiosis
PALB2 mutant male mice have reduced fertility. This reduced fertility appears to be due to germ cell attrition resulting from a combination of unrepaired DNA breaks during meiosis and defective synapsis of the X and Y chromosomes. The function of homologous recombination during meiosis appears to be repair of DNA damages, particularly double-strand breaks (also see Origin and function of meiosis). The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis. | PALB2
Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.[1][2][3]
# Function
This gene encodes a protein that functions in genome maintenance (double strand break repair). This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.[1] PALB2 binds the single strand DNA and directly interacts with the recombinase RAD51 to stimulate strand invasion, a vital step of homologous recombination,[11] (see Figure "Homologous recombinational repair of DNA double-strand damage"). PALB2 can function synergistically with a BRCA2 chimera (termed piccolo, or piBRCA2) to further promote strand invasion.[11]
# Clinical significance
Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [12] of magnitude similar to that associated with BRCA2 mutations [13] and PALB2-deficient cells are sensitive to PARP inhibitors.[11]
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer by scientists at the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. This has paved for the way for developing a new gene test for families where pancreatic cancer occurs in multiple family members.[14] Tests for PALB2 have been developed by Ambry Genetics [15] and Myriad Genetics[16] that are now available. The PALB2 Interest Group (PALB2.org) is an international consortium of scientists and clinicians who coordinate research into this gene. They are keen to hear from women and men with PALB2 mutations.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[3]
# Meiosis
PALB2 mutant male mice have reduced fertility.[17] This reduced fertility appears to be due to germ cell attrition resulting from a combination of unrepaired DNA breaks during meiosis and defective synapsis of the X and Y chromosomes. The function of homologous recombination during meiosis appears to be repair of DNA damages, particularly double-strand breaks[18] (also see Origin and function of meiosis). The PALB2-BRCA1 interaction is likely important for repairing such damages during male meiosis. | https://www.wikidoc.org/index.php/PALB2 | |
28ffde0daabc03ba1a19f847ba4a1bd258ee0342 | wikidoc | PAM16 | PAM16
Mitochondrial import inner membrane translocase subunit TIM16 also known as presequence translocated-associated motor subunit PAM16, mitochondria-associated granulocyte macrophage CSF-signaling molecule, or presequence translocated-associated motor subunit PAM16 is a protein that in humans is encoded by the PAM16 gene.
# Structure
The PAM16 gene is located on the p arm of chromosome 16 at position 13.3 and it spans 11,150 base pairs. The PAM16 gene produces a 15.1 kDa protein composed of 137 amino acids. The structure has been found to contain a 21-residue mitochondrial targeting leader sequence.
# Function
The PAM16 gene encodes for a mitochondrial protein with mutltiple functions. It is responsible for the regulation of ATP-dependent protein translocation into the mitochondrial matrix, inhibition of DNAJC19 stimulation of HSPA9/Mortalin ATPase activity, and granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Furthermore, PAM16 plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis.
# Clinical Significance
Mutations in the PAM16 gene has been shown to cause mitochondrial deficiencies and associated disorders. It is mainly associated with Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, which is an autosomal recessive disease characterized by pre- and postnatal short stature, developmental delay, dysmorphic facial appearance, narrow chest, prominent abdomen, platyspondyly, short limbs, and other abnormalities of the skeleton.
# Interactions
PAM16 has been known to interact with PAM18, DNAJC19, TIMM17A, FEZ1, TRIM25, MARC1, and other proteins. | PAM16
Mitochondrial import inner membrane translocase subunit TIM16 also known as presequence translocated-associated motor subunit PAM16, mitochondria-associated granulocyte macrophage CSF-signaling molecule, or presequence translocated-associated motor subunit PAM16 is a protein that in humans is encoded by the PAM16 gene.[1][2][3]
# Structure
The PAM16 gene is located on the p arm of chromosome 16 at position 13.3 and it spans 11,150 base pairs.[1] The PAM16 gene produces a 15.1 kDa protein composed of 137 amino acids.[4][5] The structure has been found to contain a 21-residue mitochondrial targeting leader sequence.[6]
# Function
The PAM16 gene encodes for a mitochondrial protein with mutltiple functions. It is responsible for the regulation of ATP-dependent protein translocation into the mitochondrial matrix, inhibition of DNAJC19 stimulation of HSPA9/Mortalin ATPase activity, and granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Furthermore, PAM16 plays a role in the import of nuclear-encoded mitochondrial proteins into the mitochondrial matrix and may be important in reactive oxygen species (ROS) homeostasis.[3][2][1]
# Clinical Significance
Mutations in the PAM16 gene has been shown to cause mitochondrial deficiencies and associated disorders. It is mainly associated with Megarbane-Dagher-Melike type spondylometaphyseal dysplasia, which is an autosomal recessive disease characterized by pre- and postnatal short stature, developmental delay, dysmorphic facial appearance, narrow chest, prominent abdomen, platyspondyly, short limbs, and other abnormalities of the skeleton.[2]
[3][1]
# Interactions
PAM16 has been known to interact with PAM18, DNAJC19, TIMM17A, FEZ1, TRIM25, MARC1, and other proteins.[7][2][3] | https://www.wikidoc.org/index.php/PAM16 | |
29bfe18a32ae703d1f950d295877b28020a25a00 | wikidoc | PANX1 | PANX1
Pannexin 1 is a protein in humans that is encoded by the PANX1 gene.
The protein encoded by this gene belongs to the innexin family. Innexin family members are the structural components of gap junctions. This protein and pannexin 2 are abundantly expressed in central nerve system (CNS) and are coexpressed in various neuronal populations. Studies in Xenopus oocytes suggest that this protein alone and in combination with pannexin 2 may form cell type-specific gap junctions with distinct properties.
# Clinical relevance
Truncating mutations in this gene have been shown to promote breast cancer metastasis to the lungs by allowing cancer cells to survive mechanical stretch in the microcirculation.
Disruptions of this gene have been associated to melanoma tumor progression.
Pannexin 1 is also an important component of membrane channels involved in the formation of thin plasma membrane extensions called apoptopodia and beaded apoptopodia during apoptosis. | PANX1
Pannexin 1 is a protein in humans that is encoded by the PANX1 gene.[1]
The protein encoded by this gene belongs to the innexin family. Innexin family members are the structural components of gap junctions. This protein and pannexin 2 are abundantly expressed in central nerve system (CNS) and are coexpressed in various neuronal populations. Studies in Xenopus oocytes suggest that this protein alone and in combination with pannexin 2 may form cell type-specific gap junctions with distinct properties.[1]
# Clinical relevance
Truncating mutations in this gene have been shown to promote breast cancer metastasis to the lungs by allowing cancer cells to survive mechanical stretch in the microcirculation.[2]
Disruptions of this gene have been associated to melanoma tumor progression.[3]
Pannexin 1 is also an important component of membrane channels involved in the formation of thin plasma membrane extensions called apoptopodia and beaded apoptopodia during apoptosis.[4][5] | https://www.wikidoc.org/index.php/PANX1 | |
3673527471c608900a0fd27f95eb98c749f4b480 | wikidoc | PARP1 | PARP1
Poly polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is one of the PARP family of enzymes.
# Function
PARP1 works:
- By modifying nuclear proteins by poly ADP-ribosylation.
- In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context).
PARP1 is involved in:
- Differentiation, proliferation, and tumor transformation
- Normal or abnormal recovery from DNA damage
- Maybe the site of mutation in Fanconi anemia
- The pathophysiology of type I diabetes.
PARP1 is activated by:
- Helicobacter pylori in the development and proliferation of gastric cancer.
## Role in DNA damage repair
PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with siRNA or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication, the replication fork stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination (HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR), which has also been observed in vivo in mice using the pun assay. Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.
## Over-expression in cancer
PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (MMEJ). MMEJ is associated with frequent chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements. When PARP1 is up-regulated, MMEJ is increased, causing genome instability. PARP1 is up-regulated and MMEJ is increased in tyrosine kinase-activated leukemias.
PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer, BRCA-mutated ovarian cancer, and BRCA-mutated serous ovarian cancer.
PARP1 is also over-expressed in a number of other cancers, including neuroblastoma, HPV infected oropharyngeal carcinoma, testicular and other germ cell tumors, Ewing’s sarcoma, malignant lymphoma, breast cancer, and colon cancer.
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes). (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damage which, through replication errors (translesion synthesis), lead to mutations and cancer. However, PARP1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
## Interaction with BRCA1 and BRCA2
Both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. Cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.
## Application to cancer therapy
It is hypothesized that PARP1 inhibitors may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.
## Aging
PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear leukocyte blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla elephant and man) correlates with maximum lifespan of the species. Lymphoblastoid cell lines established from blood samples of humans who were centenarians (100 years old or older) have significantly higher PARP activity than cell lines from younger (20 to 70 years old) individuals. The Wrn protein is deficient in persons with Werner syndrome, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks. These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore, PARP can also act against production of reactive oxygen species, which may contribute to longevity by inhibiting oxidative damage to DNA and proteins. These observations suggest that PARP activity contributes to mammalian longevity, consistent with the DNA damage theory of aging.
PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS). Tyrosyl tRNA synthetase translocates to the nucleus under stress conditions stimulating NAD+-dependent auto-poly-ADP-ribosylation of PARP1, thereby altering the functions of PARP1 from a chromatin architectural protein to a DNA damage responder and transcription regulator.
The messenger RNA level and protein level of PARP1 is controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1. The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter. If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.
Cells from older humans (69 to 75 years of age) have a constitutive expression level of both PARP1 and PARP2 genes reduced by half, compared to their levels in young adult humans (19 to 26 years old). However, centenarians (humans aged 100 to 107 years of age) have constitutive expression of PARP1 at levels similar to those of young individuals. This high level of PARP1 expression in centenarians was shown to allow more efficient repair of H2O2 sublethal oxidative DNA damage. Higher DNA repair is thought to contribute to longevity (see DNA damage theory of aging). The high constitutive levels of PARP1 in centenarians were thought to be due to altered epigenetic control of PARP1 expression.
# Plant PARP1
Plants have a PARP1 with substantial similarity to animal PARP1, and roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied. Intriguingly, in Arabidopsis thaliana (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis. The plant PARP2 carries PARP regulatory and catalytic domains with only intermediate similarity to PARP1, and carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.
# Interactions
PARP1 has been shown to interact with:
- APTX,
- MYBL2
- RELA,
- P53,
- POLA1,
- POLA2,
- XRCC1, and
- ZNF423. | PARP1
Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene.[1] It is one of the PARP family of enzymes.
# Function
PARP1 works:
- By modifying nuclear proteins by poly ADP-ribosylation.
- In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context).
PARP1 is involved in:
- Differentiation, proliferation, and tumor transformation
- Normal or abnormal recovery from DNA damage
- Maybe the site of mutation in Fanconi anemia[citation needed]
- The pathophysiology of type I diabetes.[2]
PARP1 is activated by:
- Helicobacter pylori in the development and proliferation of gastric cancer.[3]
## Role in DNA damage repair
PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with siRNA or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication, the replication fork stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination (HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR),[4][5][6] which has also been observed in vivo in mice using the pun assay.[7] Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.[8]
## Over-expression in cancer
PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (MMEJ).[9] MMEJ is associated with frequent chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements. When PARP1 is up-regulated, MMEJ is increased, causing genome instability.[10] PARP1 is up-regulated and MMEJ is increased in tyrosine kinase-activated leukemias.[10]
PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,[11] BRCA-mutated ovarian cancer,[12] and BRCA-mutated serous ovarian cancer.[13]
PARP1 is also over-expressed in a number of other cancers, including neuroblastoma,[14] HPV infected oropharyngeal carcinoma,[15] testicular and other germ cell tumors,[16] Ewing’s sarcoma,[17] malignant lymphoma,[18] breast cancer,[19] and colon cancer.[20]
Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[21] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[21] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damage which, through replication errors (translesion synthesis), lead to mutations and cancer. However, PARP1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.
## Interaction with BRCA1 and BRCA2
Both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. Cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.
## Application to cancer therapy
It is hypothesized that PARP1 inhibitors may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.[22][23]
## Aging
PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear leukocyte blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla elephant and man) correlates with maximum lifespan of the species.[24] Lymphoblastoid cell lines established from blood samples of humans who were centenarians (100 years old or older) have significantly higher PARP activity than cell lines from younger (20 to 70 years old) individuals.[25] The Wrn protein is deficient in persons with Werner syndrome, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks.[26] These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore, PARP can also act against production of reactive oxygen species, which may contribute to longevity by inhibiting oxidative damage to DNA and proteins.[27] These observations suggest that PARP activity contributes to mammalian longevity, consistent with the DNA damage theory of aging.[28]
PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).[29] Tyrosyl tRNA synthetase translocates to the nucleus under stress conditions stimulating NAD+-dependent auto-poly-ADP-ribosylation of PARP1,[29] thereby altering the functions of PARP1 from a chromatin architectural protein to a DNA damage responder and transcription regulator.[30]
The messenger RNA level and protein level of PARP1 is controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1.[31] The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter.[11] If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.[11][12]
Cells from older humans (69 to 75 years of age) have a constitutive expression level of both PARP1 and PARP2 genes reduced by half, compared to their levels in young adult humans (19 to 26 years old). However, centenarians (humans aged 100 to 107 years of age) have constitutive expression of PARP1 at levels similar to those of young individuals.[32] This high level of PARP1 expression in centenarians was shown to allow more efficient repair of H2O2 sublethal oxidative DNA damage.[32] Higher DNA repair is thought to contribute to longevity (see DNA damage theory of aging). The high constitutive levels of PARP1 in centenarians were thought to be due to altered epigenetic control of PARP1 expression.[32]
# Plant PARP1
Plants have a PARP1 with substantial similarity to animal PARP1, and roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied.[33][34] Intriguingly, in Arabidopsis thaliana (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.[35] The plant PARP2 carries PARP regulatory and catalytic domains with only intermediate similarity to PARP1, and carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.[35]
# Interactions
PARP1 has been shown to interact with:
- APTX,[36][37]
- MYBL2[38]
- RELA,[39]
- P53,[36][40]
- POLA1,[41]
- POLA2,[41]
- XRCC1,[36][42] and
- ZNF423.[43] | https://www.wikidoc.org/index.php/PARP1 | |
a7098388f7286f8a479d59d00dfe8dce45c80ca2 | wikidoc | PARP2 | PARP2
Poly polymerase 2 is an enzyme that in humans is encoded by the PARP2 gene. It is one of the PARP family of enzymes.
# Function
This gene encodes poly(ADP-ribosyl)transferase-like 2 protein, which contains a catalytic domain and is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. The basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein. Two alternatively spliced transcript variants encoding distinct isoforms have been found.
In the plant species Arabidopsis thaliana, PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis. The plant PARP2 carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.
# PARP inhibitor drugs
Some PARP inhibitor anti-cancer drugs (primarily aimed at PARP1) also inhibit PARP2, e.g. niraparib.
# Interactions
PARP2 has been shown to interact with XRCC1. | PARP2
Poly [ADP-ribose] polymerase 2 is an enzyme that in humans is encoded by the PARP2 gene.[1][2][3] It is one of the PARP family of enzymes.
# Function
This gene encodes poly(ADP-ribosyl)transferase-like 2 protein, which contains a catalytic domain and is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. The basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein. Two alternatively spliced transcript variants encoding distinct isoforms have been found.[3]
In the plant species Arabidopsis thaliana, PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.[4] The plant PARP2 carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.[4]
# PARP inhibitor drugs
Some PARP inhibitor anti-cancer drugs (primarily aimed at PARP1) also inhibit PARP2, e.g. niraparib.
# Interactions
PARP2 has been shown to interact with XRCC1.[5] | https://www.wikidoc.org/index.php/PARP2 | |
83fbd7d09dc8734c70f2d2b12c7122c225eff78d | wikidoc | PBDC1 | PBDC1
CXorf26 (Chromosome X Open Reading Frame 26), also known as MGC874, is a well conserved human gene found on the plus strand of the short arm of the X chromosome. The exact function of the gene is poorly understood, but the polysaccharide biosynthesis domain that spans a major portion of the protein product (known as UPF0368), as well as the yeast homolog, YPL225, offer insights into its possible function.
# Proposed function
Given the mass of data available on CXorf26, potential function is likely related to the workings of RNA polymerase II, ubiquitination, and ribosomes in the cytoplasm. The basis of these arguments is on the interaction data of human CXorf26 as well as its yeast homolog, YPL225W. Both homologs show interaction with multiple ubiquinated proteins as well as the transcriptional enzyme RNA polymerase II. For example, ubiquitiation and subsequent degradation of the 26S proteasome serves an important function in regulating transcription in eukaryotes. The yeast protein RPN11, which interacts with YPL225W, has a homolog in humans that is a metalloprotease component of 26S proteasome that also degrades proteins targeted for destruction by the ubiquitin pathway. These functions do not seem to relate to a polysaccharide biosynthesis function as would be assumed due to its conserved domain, but it may still play a role in secondary structure or sites of phosphorylation.
Further experimentation into the potential role of CXorf26 can give further insight into its exact function in these key cellular processes. Experiments such as a RNA polymerase II inhibitior and subsequent gene expression of CXorf26 could enlighten potential function as well as a complete knoockout of YPL225W in yeast using methods such as RNAi.
# Gene
CXorf26 is found on the plus strand of the short arm of the X chromosome, specifically on the gene locus Xq13.3 spanning the genomic chromosome region from bases 75,393,420-75,397,740. The primary mRNA transcript sequence has 1214 base pairs and its protein product, UPF0368,is composed of 233 amino acids and has a predicted mass of 26,057 Da.
The locus where CXorf26 is located, Xq13.3, has known associations to X-linked mental retardation.
The third gene located upstream of CXorf26 is ATRX, which encodes for an ATPase/helicase domain, and when mutated causes an X-linked mental retardation syndrome along with alpha thalassemia syndrome; both are known to cause changes in the DNA methylation patterns. Furthermore, the third gene downstream of CXorf26, ZDHHC15, which when mutated, causes mental retardation X-linked type 91. One noteworthy gene located nearby is Xist, which plays a role in the inactivation process of the X chromosome. X inactivation relates to CXorf26, and is discussed below in the relevant research section.
# Expression
Expression data for CXorf26 shows it is highly ubiquitously expressed throughout human tissues and ESTs in nearly all situations. The GEO profile to the right shows the expression levels for CXorf26 in common human tissues to consistently be around the 75th percentile range, suggesting it may possess a housekeeping function due its seemingly ubiquitous expression. If the conserved domain does indeed play a role in polysaccharide biosynthesis of some sort, this high gene expression is sensible to that function.
Gene expression profiles in the Gene Expression Omnibus (GEO) repository located within the NCBI website demonstrated that there were not many treatments that resulted in a changing of expression of CXorf26 in examined tissues. However, one experiment compared CXorf26 expression in lung adenocarcinoma CL1-5 cells either overexpressing or underexpressing Claudin-1. Results indicated that CXorf26 expression greatly drops when CLDN1 is overexpressed. CLDN1 is a major component in forming tight junction complexes between cells, which foster cell-cell adhesion of cell membranes. More tight junctions formed by CLDN1 would likely result in decreased expression of CXorf26 since the cell membrane would be used for tight junctions instead of its normal function related to heparan sulfate.
## Alternative splice forms
There is only one alternative splice form for CXorf26. This splice form has significantly fewer mRNA base pairs at 977, but still has a protein product of 232 amino acids. This alternative splice form appears to be missing exon 5 of the transcript, but it may be added onto exon 6, creating a larger exon compared to the consensus transcript.
There were no other predicted exons within the genomic CXorf26 sequence when 3000 base pairs were added on either side in the search.
## Promoter region
The promoter for CXorf26 is predicted to be located from bases 75392235 to 75393075 on the X chromosome positive strand. The promoter region has extensive conservation with all primates and most mammal homologs, but conservation is lessened in more distantly related species. Given the primary transcript begins at base 7539277, the promoter overlaps with it by 304 bases. 20 predicted transcription factor binding sites with their transcription factor family was collected as well. A high amount of the transcriptional factors relate to zinc finger factors, which have the function of stabilizing protein folds, while none of the factors seem to relate to a potential polysaccharide biosynthesis function. One transcription factor family predicted to bind to the promoter region was V$CHRF, and is involved in regulation of the cell cycle. The regulation could be related to ubiquitin function; proteins with ubiquitination type function were found to interact with CXorf26.
# Protein
## Subcellular distribution
The CXorf26 protein is 56.5% likely to be localized within the cytoplasm while 17.4% likely to localized to the mitochondria. CXorf26's yeast homolog, YPL225W, was GFP tagged and its location was determined to be in the cytoplasm. Cytoplasmic location instead of transmembrane was supported since no hydrophobic signal peptide sequence and TMAP predicted no potential transmembrane segments in CXorf26 or any of its homologs in other species.
## Polysaccharide domain
CXorf26 was found to have conserved domain known as DUF757 within its sequence. The conserved domain spans a majority of the protein sequence, from amino acids 39-159. Conservation of the domain is strong throughout all homologs compared, including mammals, invertebrates such as insects, and even sponges. The yeast homolog, YPL225W, shows 42.4% identity and 62% similarity in this domain. Conservation of the domain is especially high in areas which include one of the multiple alpha helices or beta sheets. There are also multiple conserved phosphorylation sites located in the amino acid sequence at tyrosine 72 and serine 126.
According to NCBI, this domain is in the Pfam PF04669 family of proteins expected play a role in xylan biosynthesis in plant cell walls, but its exact role in the synthesis pathway is unknown. As animal cells do not contain cell walls, its exact function in other organisms such as humans is unknown.
Xylan is made from units of the pentose sugar xylose, which is known for being the first saccharide in multiple biosynthetic pathways of anionic polysaccharides such as heparan sulfate and chondroitin sulfate. Like Xylan, heparan sulfate it is found on the cell surface; since it is needed for both the cell surface and extracellular matrix,it may explain CXorf26's high expression in nearly all human tissues. Heparan biosynthesis occurs in the lumen of the endoplasmic reticulum and is initiated by the transfer of a xylose from UDP-xylose by xylosyltransferase to specific serine residues within the protein core. PSORTII predicts the presence of a KKXX-like motif, GEKA, near the C-terminus of CXorf26. KKXX-like motifs are predicted endoplasmic reticulum membrane retention signals. This motif is only conserved in primates. However, another KKXX-like motif, QDKE, is found to exist at the end of the domain. The K in this motif is highly conserved back to most invertebrates. However, contradicting results from NetNGlyc predicted no N-glycosylation sites, suggesting CXorf26 does not undergo special folding in the endoplasmic reticulum lumen. Given that the conserved domain cannot function to create xylan since there are no cell walls in animal cells, the function may be related to this pathway.
## Secondary structure
Predictions across multiple programs suggest the presence of 7 alpha helices and 2 beta sheets for CXorf26; the majority of the secondary structures are in the conserved domain. Experimental evidence in the yeast homolog shows 4 alpha helices and 2 beta sheets all in the polysaccharide domain, just as the predicted SWISS model above shows for humans. The location of the secondary structures are also conserved.
## Post-translational modifications
Pepsin (pH 1.3), Asp-N endopeptidase, N-terminal Glutamate and Proteinase K all had 50 or more cleavage sites within the protein, but none of the 10 caspases had any cleavage sites. This suggests CXorf26 is not likely to be cleaved or degraded during apoptosis. This follows with the observation that CXorf26 is expressed highly in nearly all tissues and experimental conditions.
Lysine 63 and 66 are potential sites of glycation of epsilon amino groups of lysines. Lysine 63 was conserved in both Macaca mulatta and Bombus impatiens. There are 10 serine, 3 threonine, and 6 tyrosine phosphorylation sites predicted within the CXorf26 protein. When comparing the predicted phosphorylation sites, those shown in the table below were those conserved in Macaca mulatta as well as Bombus impatiens. S127 was left in the table even though Homo sapiens and Macaca mulatta did not have significant scores above threshold for that position. Through evolutionary change, the serine in Bombus was changed to a tyrosine in Homo sapiens and Macaca mulatta, which is still capable of phosphorylation, suggesting although there was a mutation, it would likely not result in a large change for the protein and its function.
# Species distribution
CXorf26 is strongly evolutionary conserved, with conservation found in Batrachochytrium dendrobatidis. A multiple sequence alignment of 20 orthologous protein sequences reveals very strong conservation of the polysaccharide biosynthesis domain, but conservation after it was essentially non-existent in invertebrates. For those vertebrates that contained a sequence after the conserved domain, it was found to be of low complexity and filled with repetitive sequence of the amino acid motif 'GEK', corresponding to amino acids glycine, glutamic acid, and lysine. Glutamic acid and lysine both are charged, which contributes to the overall hydrophilicity of the section after the conserved domain.
## Yeast homolog YPL225W
The CXorf26 homolog in yeast, YPL225W, has an overall identity match of 27% but a 42.4% identity and 62% similarity with the polysaccharide biosynthesis domain. Like the predicted human secondary structure, YPL225W is experimentally verified to also contain four alpha helices and two beta sheets within the biosynthesis domain. Like CXorf26, YPL225W function in yeast is unknown, but based on co-purification experiments it may interact with ribosomes since many of its 18 interacting proteins were related to RNA and ribosomes. There were also multiple proteins involved with RNA polymerase, which is involved in the cellular process of transcription. Furthermore, multiple proteins were involved in ubiquitination. Some of the interacting yeast proteins with the higher interaction scores were UBI4, RPB8, SRO9, and NAB2.
# Interacting proteins
Potential interacting proteins were identified using the tools provided at the I2D Interlogous Interaction Database and the STRING 9.0 program. Although more proteins were predicted, those shown below had the highest scores and showed the greatest possibility of relating to potential CXorf26 function.
SMAD2, PHB, and CTNNB1 were found in an experiment investigating transcriptional factor networks. The BABAM1 interaction was found in both databases using an anti-tag coimmunoprecipitation assay while POLR2H was based on a tandem affinity purification assay using the yeast homolog, YPL225W. | PBDC1
CXorf26 (Chromosome X Open Reading Frame 26), also known as MGC874, is a well conserved human gene found on the plus strand of the short arm of the X chromosome. The exact function of the gene is poorly understood, but the polysaccharide biosynthesis domain that spans a major portion of the protein product (known as UPF0368), as well as the yeast homolog, YPL225, offer insights into its possible function.
# Proposed function
Given the mass of data available on CXorf26, potential function is likely related to the workings of RNA polymerase II, ubiquitination, and ribosomes in the cytoplasm. The basis of these arguments is on the interaction data of human CXorf26 as well as its yeast homolog, YPL225W. Both homologs show interaction with multiple ubiquinated proteins as well as the transcriptional enzyme RNA polymerase II. For example, ubiquitiation and subsequent degradation of the 26S proteasome serves an important function in regulating transcription in eukaryotes.[1] The yeast protein RPN11, which interacts with YPL225W, has a homolog in humans that is a metalloprotease component of 26S proteasome that also degrades proteins targeted for destruction by the ubiquitin pathway.[2] These functions do not seem to relate to a polysaccharide biosynthesis function as would be assumed due to its conserved domain, but it may still play a role in secondary structure or sites of phosphorylation.
Further experimentation into the potential role of CXorf26 can give further insight into its exact function in these key cellular processes. Experiments such as a RNA polymerase II inhibitior and subsequent gene expression of CXorf26 could enlighten potential function as well as a complete knoockout of YPL225W in yeast using methods such as RNAi.
# Gene
CXorf26 is found on the plus strand of the short arm of the X chromosome, specifically on the gene locus Xq13.3 spanning the genomic chromosome region from bases 75,393,420-75,397,740.[3] The primary mRNA transcript sequence has 1214 base pairs and its protein product, UPF0368,is composed of 233 amino acids and has a predicted mass of 26,057 Da.[3]
The locus where CXorf26 is located, Xq13.3, has known associations to X-linked mental retardation.[4]
The third gene located upstream of CXorf26 is ATRX, which encodes for an ATPase/helicase domain, and when mutated causes an X-linked mental retardation syndrome along with alpha thalassemia syndrome; both are known to cause changes in the DNA methylation patterns.[5] Furthermore, the third gene downstream of CXorf26, ZDHHC15, which when mutated, causes mental retardation X-linked type 91.[6] One noteworthy gene located nearby is Xist, which plays a role in the inactivation process of the X chromosome. X inactivation relates to CXorf26, and is discussed below in the relevant research section.
# Expression
Expression data for CXorf26 shows it is highly ubiquitously expressed throughout human tissues and ESTs in nearly all situations. The GEO profile to the right shows the expression levels for CXorf26 in common human tissues to consistently be around the 75th percentile range, suggesting it may possess a housekeeping function due its seemingly ubiquitous expression. If the conserved domain does indeed play a role in polysaccharide biosynthesis of some sort, this high gene expression is sensible to that function.
Gene expression profiles in the Gene Expression Omnibus (GEO) repository located within the NCBI website demonstrated that there were not many treatments that resulted in a changing of expression of CXorf26 in examined tissues. However, one experiment compared CXorf26 expression in lung adenocarcinoma CL1-5 cells either overexpressing or underexpressing Claudin-1. Results indicated that CXorf26 expression greatly drops when CLDN1 is overexpressed.[8] CLDN1 is a major component in forming tight junction complexes between cells, which foster cell-cell adhesion of cell membranes.[9] More tight junctions formed by CLDN1 would likely result in decreased expression of CXorf26 since the cell membrane would be used for tight junctions instead of its normal function related to heparan sulfate.
## Alternative splice forms
There is only one alternative splice form for CXorf26. This splice form has significantly fewer mRNA base pairs at 977, but still has a protein product of 232 amino acids.[10] This alternative splice form appears to be missing exon 5 of the transcript, but it may be added onto exon 6, creating a larger exon compared to the consensus transcript.
There were no other predicted exons within the genomic CXorf26 sequence when 3000 base pairs were added on either side in the search.[11]
## Promoter region
The promoter for CXorf26 is predicted to be located from bases 75392235 to 75393075 on the X chromosome positive strand.[12] The promoter region has extensive conservation with all primates and most mammal homologs, but conservation is lessened in more distantly related species. Given the primary transcript begins at base 7539277, the promoter overlaps with it by 304 bases. 20 predicted transcription factor binding sites with their transcription factor family was collected as well. A high amount of the transcriptional factors relate to zinc finger factors, which have the function of stabilizing protein folds, while none of the factors seem to relate to a potential polysaccharide biosynthesis function. One transcription factor family predicted to bind to the promoter region was V$CHRF, and is involved in regulation of the cell cycle. The regulation could be related to ubiquitin function; proteins with ubiquitination type function were found to interact with CXorf26.
# Protein
## Subcellular distribution
The CXorf26 protein is 56.5% likely to be localized within the cytoplasm [13] while 17.4% likely to localized to the mitochondria. CXorf26's yeast homolog, YPL225W, was GFP tagged and its location was determined to be in the cytoplasm.[14] Cytoplasmic location instead of transmembrane was supported since no hydrophobic signal peptide sequence and TMAP[15] predicted no potential transmembrane segments in CXorf26 or any of its homologs in other species.
## Polysaccharide domain
CXorf26 was found to have conserved domain known as DUF757 within its sequence.[16] The conserved domain spans a majority of the protein sequence, from amino acids 39-159. Conservation of the domain is strong throughout all homologs compared, including mammals, invertebrates such as insects, and even sponges. The yeast homolog, YPL225W, shows 42.4% identity and 62% similarity in this domain. Conservation of the domain is especially high in areas which include one of the multiple alpha helices or beta sheets. There are also multiple conserved phosphorylation sites located in the amino acid sequence at tyrosine 72 and serine 126.
According to NCBI,[17] this domain is in the Pfam PF04669 family of proteins expected play a role in xylan biosynthesis in plant cell walls, but its exact role in the synthesis pathway is unknown. As animal cells do not contain cell walls, its exact function in other organisms such as humans is unknown.
Xylan is made from units of the pentose sugar xylose, which is known for being the first saccharide in multiple biosynthetic pathways of anionic polysaccharides such as heparan sulfate and chondroitin sulfate. Like Xylan, heparan sulfate it is found on the cell surface;[18] since it is needed for both the cell surface and extracellular matrix,it may explain CXorf26's high expression in nearly all human tissues. Heparan biosynthesis occurs in the lumen of the endoplasmic reticulum[19] and is initiated by the transfer of a xylose from UDP-xylose by xylosyltransferase to specific serine residues within the protein core. PSORTII predicts the presence of a KKXX-like motif, GEKA, near the C-terminus of CXorf26. KKXX-like motifs are predicted endoplasmic reticulum membrane retention signals. This motif is only conserved in primates. However, another KKXX-like motif, QDKE, is found to exist at the end of the domain. The K in this motif is highly conserved back to most invertebrates. However, contradicting results from NetNGlyc predicted no N-glycosylation sites, suggesting CXorf26 does not undergo special folding in the endoplasmic reticulum lumen.[20] Given that the conserved domain cannot function to create xylan since there are no cell walls in animal cells, the function may be related to this pathway.
## Secondary structure
Predictions across multiple programs suggest the presence of 7 alpha helices and 2 beta sheets for CXorf26; the majority of the secondary structures are in the conserved domain. Experimental evidence in the yeast homolog shows 4 alpha helices and 2 beta sheets all in the polysaccharide domain,[21] just as the predicted SWISS model above shows for humans. The location of the secondary structures are also conserved.
## Post-translational modifications
Pepsin (pH 1.3), Asp-N endopeptidase, N-terminal Glutamate and Proteinase K all had 50 or more cleavage sites within the protein, but none of the 10 caspases had any cleavage sites.[22] This suggests CXorf26 is not likely to be cleaved or degraded during apoptosis. This follows with the observation that CXorf26 is expressed highly in nearly all tissues and experimental conditions.
Lysine 63 and 66 are potential sites of glycation of epsilon amino groups of lysines.[23] Lysine 63 was conserved in both Macaca mulatta and Bombus impatiens. There are 10 serine, 3 threonine, and 6 tyrosine phosphorylation sites predicted within the CXorf26 protein. When comparing the predicted phosphorylation sites, those shown in the table below were those conserved in Macaca mulatta as well as Bombus impatiens. S127 was left in the table even though Homo sapiens and Macaca mulatta did not have significant scores above threshold for that position. Through evolutionary change, the serine in Bombus was changed to a tyrosine in Homo sapiens and Macaca mulatta, which is still capable of phosphorylation, suggesting although there was a mutation, it would likely not result in a large change for the protein and its function.
# Species distribution
CXorf26 is strongly evolutionary conserved,[24] with conservation found in Batrachochytrium dendrobatidis. A multiple sequence alignment of 20 orthologous protein sequences reveals very strong conservation of the polysaccharide biosynthesis domain, but conservation after it was essentially non-existent in invertebrates.[25] For those vertebrates that contained a sequence after the conserved domain, it was found to be of low complexity and filled with repetitive sequence of the amino acid motif 'GEK', corresponding to amino acids glycine, glutamic acid, and lysine. Glutamic acid and lysine both are charged, which contributes to the overall hydrophilicity of the section after the conserved domain.
## Yeast homolog YPL225W
The CXorf26 homolog in yeast, YPL225W, has an overall identity match of 27% but a 42.4% identity and 62% similarity with the polysaccharide biosynthesis domain. Like the predicted human secondary structure, YPL225W is experimentally verified to also contain four alpha helices and two beta sheets within the biosynthesis domain.[26] Like CXorf26, YPL225W function in yeast is unknown, but based on co-purification experiments it may interact with ribosomes since many of its 18 interacting proteins were related to RNA and ribosomes. There were also multiple proteins involved with RNA polymerase, which is involved in the cellular process of transcription. Furthermore, multiple proteins were involved in ubiquitination. Some of the interacting yeast proteins with the higher interaction scores were UBI4, RPB8, SRO9, and NAB2.
# Interacting proteins
Potential interacting proteins were identified using the tools provided at the I2D Interlogous Interaction Database[27] and the STRING 9.0 program.[28] Although more proteins were predicted, those shown below had the highest scores and showed the greatest possibility of relating to potential CXorf26 function.
SMAD2, PHB, and CTNNB1 were found in an experiment investigating transcriptional factor networks.[29] The BABAM1 interaction was found in both databases using an anti-tag coimmunoprecipitation assay[30] while POLR2H was based on a tandem affinity purification assay using the yeast homolog, YPL225W.[31] | https://www.wikidoc.org/index.php/PBDC1 | |
0a0e97df1456b7a47d208c5c70298585d03a9f8d | wikidoc | PBRM1 | PBRM1
Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.
# Structure and function
Component of the SWI/SNF-B (PBAF) chromatin-remodeling complex, which contains at least SMARCA4/BRG1, SMARCB1/SNF5/INI1/BAF47, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, and actin.
Chicken PB1 possesses 5 bromodomains, 2 bromo-adjacent homology (BAH) domains, and 1 truncated high-mobility group (HMG) motif. cPB1 is also homologous to yeast Rsc1, Rsc2, and Rsc4, essential proteins that are required for cell cycle progression through mitosis.
# Clinical significance
PBRM1 is a tumor suppressor gene in many cancer subtypes. Mutations are especially prevalent in clear cell renal cell carcinoma. | PBRM1
Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 gene.[1][2][3]
# Structure and function
Component of the SWI/SNF-B (PBAF) chromatin-remodeling complex, which contains at least SMARCA4/BRG1, SMARCB1/SNF5/INI1/BAF47, ACTL6A/BAF53A or ACTL6B/BAF53B, SMARCE1/BAF57, SMARCD1/BAF60A, SMARCD2/BAF60B, and actin.[4]
Chicken PB1 possesses 5 bromodomains, 2 bromo-adjacent homology (BAH) domains, and 1 truncated high-mobility group (HMG) motif. cPB1 is also homologous to yeast Rsc1, Rsc2, and Rsc4, essential proteins that are required for cell cycle progression through mitosis.[1]
# Clinical significance
PBRM1 is a tumor suppressor gene in many cancer subtypes.[5] Mutations are especially prevalent in clear cell renal cell carcinoma.[6] | https://www.wikidoc.org/index.php/PBRM1 | |
33a54e48de1ac6dacae62eb12a061cb2e82b7be4 | wikidoc | PCBP2 | PCBP2
Poly(rC)-binding protein 2 is a protein that in humans is encoded by the PCBP2 gene.
# Function
The protein encoded by this gene appears to be multifunctional. It along with PCBP-1 and hnRNPK corresponds to the major cellular poly(rC)-binding proteins. It contains three K-homologous (KH) domains which may be involved in RNA binding. This encoded protein together with PCBP-1 also functions as translational coactivators of poliovirus RNA via a sequence-specific interaction with stem-loop IV of the IRES and promote poliovirus RNA replication by binding to its 5'-terminal cloverleaf structure. It has also been implicated in translational control of the 15-lipoxygenase mRNA, human Papillomavirus type 16 L2 mRNA, and hepatitis A virus RNA. The encoded protein is also suggested to play a part in formation of a sequence-specific alpha-globin mRNP complex which is associated with alpha-globin mRNA stability. This multiexon structural mRNA is thought to be retrotransposed to generate PCBP-1 intronless gene which has similar functions. This gene and PCBP-1 has paralogues PCBP3 and PCBP4 which is thought to arose as a result of duplication events of entire genes. It also has two processed pseudogenes PCBP2P1 and PCBP2P2. There are presently two alternatively spliced transcript variants described for this gene.
In humans, the PCBP2 gene overlaps with TUC338, a transcribed ultra-conserved element implicated in Hepatocellular carcinoma.
# Interactions
PCBP2 has been shown to interact with HNRPK, PTBP1, and HNRNPL. | PCBP2
Poly(rC)-binding protein 2 is a protein that in humans is encoded by the PCBP2 gene.[1]
# Function
The protein encoded by this gene appears to be multifunctional. It along with PCBP-1 and hnRNPK corresponds to the major cellular poly(rC)-binding proteins. It contains three K-homologous (KH) domains which may be involved in RNA binding. This encoded protein together with PCBP-1 also functions as translational coactivators of poliovirus RNA via a sequence-specific interaction with stem-loop IV of the IRES and promote poliovirus RNA replication by binding to its 5'-terminal cloverleaf structure. It has also been implicated in translational control of the 15-lipoxygenase mRNA, human Papillomavirus type 16 L2 mRNA, and hepatitis A virus RNA. The encoded protein is also suggested to play a part in formation of a sequence-specific alpha-globin mRNP complex which is associated with alpha-globin mRNA stability. This multiexon structural mRNA is thought to be retrotransposed to generate PCBP-1 intronless gene which has similar functions. This gene and PCBP-1 has paralogues PCBP3 and PCBP4 which is thought to arose as a result of duplication events of entire genes. It also has two processed pseudogenes PCBP2P1 and PCBP2P2. There are presently two alternatively spliced transcript variants described for this gene.[2]
In humans, the PCBP2 gene overlaps with TUC338, a transcribed ultra-conserved element implicated in Hepatocellular carcinoma.[3]
# Interactions
PCBP2 has been shown to interact with HNRPK,[4] PTBP1,[4] and HNRNPL.[4] | https://www.wikidoc.org/index.php/PCBP2 | |
f71d7f8a4f770e00e673b70e9e8f9107ad15db18 | wikidoc | PCDHY | PCDHY
PCDH11Y is a gene unique to human males that encodes Protocadherin 11Y, a protein that guides the development of nerve cells. PCDH11X, located on the X chromosome, is common, in both sexes, to humans and our nearest relative, the chimpanzee; however, PCDH11Y, located on the Y chromosome, is unique to males.
In terms of human evolution, it has been estimated that pcdh11x "gene jumped" from X to Y around three million years ago; coincident with increased human brain size and the first use of tools. Furthermore, around 120,000 to 200,000 years ago, the PCDH11Y gene was able to further transform, splitting in half and reversing its position.
PCDH11X/Y are cadherin family genes. They make proteins, involved in signalling, that attach to the surface of nerve cells. PCDH11X and PCDH11Y, respond in different ways to Retinoic acid, a chemical involved in the development of embryos. The acid stimulates the activity of PCDH11Y but suppresses PCDH11X. This is likely one of the explanations for the differences between the brains of men and women.
Psychiatrist, professor Tim Crow, also believes the gene explains lateralisation. Humans have "lateralised" brains, in which the different sides became specialised for particular jobs. For instance 90% of people will use their right hands for fiddly tasks. A chimpanzee is just as likely to use either hand. It also explains why, for right-handed people, linguistic functions are concentrated on the left side of the brain. | PCDHY
PCDH11Y is a gene unique to human males that encodes Protocadherin 11Y, a protein that guides the development of nerve cells. PCDH11X, located on the X chromosome, is common, in both sexes, to humans and our nearest relative, the chimpanzee; however, PCDH11Y, located on the Y chromosome, is unique to males.[1]
In terms of human evolution, it has been estimated that pcdh11x "gene jumped" from X to Y around three million years ago; coincident with increased human brain size and the first use of tools. Furthermore, around 120,000 to 200,000 years ago, the PCDH11Y gene was able to further transform, splitting in half and reversing its position.[2]
PCDH11X/Y are cadherin family genes. They make proteins, involved in signalling, that attach to the surface of nerve cells.[2] PCDH11X and PCDH11Y, respond in different ways to Retinoic acid, a chemical involved in the development of embryos. The acid stimulates the activity of PCDH11Y but suppresses PCDH11X. This is likely one of the explanations for the differences between the brains of men and women.[1]
Psychiatrist, professor Tim Crow, also believes the gene explains lateralisation. Humans have "lateralised" brains, in which the different sides became specialised for particular jobs. For instance 90% of people will use their right hands for fiddly tasks. A chimpanzee is just as likely to use either hand. It also explains why, for right-handed people, linguistic functions are concentrated on the left side of the brain.[1] | https://www.wikidoc.org/index.php/PCDHY | |
f0be6ba2d696dae85e3f55fd2959bf059cc8ac0d | wikidoc | PCSK5 | PCSK5
Proprotein convertase subtilisin/kexin type 5 is an enzyme that in humans is encoded by the PCSK5 gene, found in chromosome 9q21.3 Two alternatively spliced transcripts are described for this gene but only one has its full length nature known.
# Function
The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein mediates posttranslational endoproteolytic processing for several integrin alpha subunits. It is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160.
# Clinical significance
Mutations in this gene have been associated with Currarino syndrome-like malformations. | PCSK5
Proprotein convertase subtilisin/kexin type 5 is an enzyme that in humans is encoded by the PCSK5 gene, found in chromosome 9q21.3[1][2][3] Two alternatively spliced transcripts are described for this gene but only one has its full length nature known.
# Function
The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein mediates posttranslational endoproteolytic processing for several integrin alpha subunits. It is thought to process prorenin, pro-membrane type-1 matrix metalloproteinase and HIV-1 glycoprotein gp160.[3]
# Clinical significance
Mutations in this gene have been associated with Currarino syndrome-like malformations.[4] | https://www.wikidoc.org/index.php/PCSK5 | |
522f20ed05b5429b0aa26c6b1d87fd08da2913e1 | wikidoc | PCSK6 | PCSK6
Proprotein convertase subtilisin/kexin type 6 is an enzyme that in humans is encoded by the PCSK6 gene. PCSK6 is a protease that cleaves NODAL into an active form to help trigger the development of left/right (LR) asymmetry. It may also be involved in left and right handedness in humans.
# Function
The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can cleave precursor protein at their paired basic amino acid processing sites. Some of its substrates are - transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. Alternatively spliced transcript variants encoding different isoforms have been identified.
PCSK6 also cleaves and activates corin, a serine protease that regulates sodium homeostasis and blood pressure.
# Clinical significance
This gene is thought to play a role in tumor progression.
PCSK6 deficiency causes salt-sensitive hypertension in mice. | PCSK6
Proprotein convertase subtilisin/kexin type 6 is an enzyme that in humans is encoded by the PCSK6 gene.[1][2] PCSK6 is a protease that cleaves NODAL into an active form to help trigger the development of left/right (LR) asymmetry.[3] It may also be involved in left and right handedness in humans.[4][5][6]
# Function
The protein encoded by this gene belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can cleave precursor protein at their paired basic amino acid processing sites. Some of its substrates are - transforming growth factor beta related proteins, proalbumin, and von Willebrand factor. Alternatively spliced transcript variants encoding different isoforms have been identified.[2]
PCSK6 also cleaves and activates corin, a serine protease that regulates sodium homeostasis and blood pressure.[7]
# Clinical significance
This gene is thought to play a role in tumor progression.[2]
PCSK6 deficiency causes salt-sensitive hypertension in mice.[7] | https://www.wikidoc.org/index.php/PCSK6 | |
8c4cdcda0e541c2f00263aeb6d27d0d0034ed074 | wikidoc | PCSK9 | PCSK9
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.
PCSK9 is ubiquitously expressed in many tissues and cell types. PCSK9 binds to the receptor for low-density lipoprotein particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid. The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid. Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.
PCSK9 has medical importance because it acts in lipoprotein homeostasis. Agents which block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015, was $14,000 per year at full retail; judged of unclear cost effectiveness by some. While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.
## History
In February 2003, Nabil Seidah, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1. Meanwhile, a lab led by Catherine Boileau at the Necker-Enfants Malades Hospital in Paris had been following families with familial hypercholesterolaemia, a genetic condition that, in 90% of cases causes coronary artery disease (FRAMINGHAM study) and in 60% of cases may lead to an early death; they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition. In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol. Meanwhile, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples. With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.
In July 2015, the FDA approved the first PCSK9 Inhibitor drugs for medical use.
# Structure
## Gene
The PCSK9 gene resides on chromosome 1 at the band 1p32.3 and includes 13 exons. This gene produces two isoforms through alternative splicing.
## Protein
PCSK9 is a member of the peptidase S8 family.
The solved structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1-30); the N-terminal prodomain (residues 31-152); the catalytic domain (residues 153-425); and the C-terminal domain (residues 426-692), which is further divided into three modules. The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR, a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR. The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61-70 in the N-terminal prodomain are crucial for its autoprocessing.
# Function
## Role and regulatory function
This protein plays a major regulatory role in cholesterol homeostasis, mainly by reducing LDLR levels on the plasma membrane. Reduced LDLR levels result in decreased metabolism of LDL-particles, which could lead to hypercholesterolemia. When LDL binds to LDLR, it induces internalization of LDLR-LDL complex within an endosome. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation. The conformational change causes LDLR to release its LDL ligand, and the receptor is recycled back to the plasma membrane. However, when PCSK9 binds to the LDLR (through the EGF-A domain), PCSK9 prevents the conformational change of the receptor-ligand complex. This inhibition redirects the LDLR to the lysosome instead.
PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase. PCSK9 is expressed mainly in the liver, the intestine, the kidney, and the central nervous system. PCSK9 also plays an important role in intestinal triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.
After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9. In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a diurnal rhythm similar to cholesterol synthesis. The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role. PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2), which also controls LDLR expression.
PCSK9 may also have a role in the differentiation of cortical neurons.
## Clinical significance
Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including liver cells, and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR. If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.
Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3). The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.
In humans, PCSK9 was initially discovered as a protein expressed in the brain. However, it has also been described in the kidney, the pancreas, liver and small intestine. Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis. Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis.
As PCSK9 binds to LDLR, which prevents the removal of LDL-particles from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia). Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.
In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity, regulation of re-absorption of sodium in the kidney which is relevant in hypertension. Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis. In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system. PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum.
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
# PCSK9 Inhibitor Drugs
Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia). Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.
PCSK9 inhibitor drugs are now approved by the FDA to treat familial hypercholesterolemia.
## As a drug target
Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs. Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic inclisiran. PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.
A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks. However more recent reviews conclude that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals, PCSK9 inhibitor use probably results in little or no difference in mortality.
Regeneron (in collaboration with Sanofi) became the first to market a PCSK9 inhibitor, with a competitor Amgen reaching market slightly later. The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous familial hypercholesterolemia which causes high cholesterol levels and heart attacks at a young age.
### Warning
An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.
## Monoclonal antibodies
A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Aventis/Regeneron). As of July 2015, the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.
A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.
## Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.
## Gene silencing
The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice. A locked nucleic acid reduced PCSK9 mRNA levels in mice. Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.
## Vaccination
A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP's are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.
## Naturally occurring inhibitors
The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro, and lowers serum PCSK9 in mice and hamsters in vivo. It has been speculated that this action contributes to the ability of berberine to lower serum cholesterol. Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity. | PCSK9
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1.[1] It is the 9th member of the proprotein convertase family of proteins that activate other proteins.[2] Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme.[3] The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.[4]
PCSK9 is ubiquitously expressed in many tissues and cell types.[5] PCSK9 binds to the receptor for low-density lipoprotein particles (LDL), which typically transport 3,000 to 6,000 fat molecules (including cholesterol) per particle, within extracellular fluid. The LDL receptor (LDLR), on liver and other cell membranes, binds and initiates ingestion of LDL-particles from extracellular fluid into cells, thus reducing LDL particle concentrations. If PCSK9 is blocked, more LDLRs are recycled and are present on the surface of cells to remove LDL-particles from the extracellular fluid.[6] Therefore, blocking PCSK9 can lower blood LDL-particle concentrations.[7][8]
PCSK9 has medical importance because it acts in lipoprotein homeostasis. Agents which block PCSK9 can lower LDL particle concentrations. The first two PCSK9 inhibitors, alirocumab and evolocumab, were approved as once every two week injections, by the U.S. Food and Drug Administration in 2015 for lowering LDL-particle concentrations when statins and other drugs were not sufficiently effective or poorly tolerated. The cost of these new medications, as of 2015[update], was $14,000 per year at full retail; judged of unclear cost effectiveness by some.[9] While these medications are prescribed by many physicians, the payment for prescriptions are often denied by insurance providers.[10][11][12]
## History
In February 2003, Nabil Seidah, a scientist at the Clinical Research Institute of Montreal in Canada, discovered a novel human proprotein convertase, the gene for which was located on the short arm of chromosome 1.[13] Meanwhile, a lab led by Catherine Boileau at the Necker-Enfants Malades Hospital in Paris had been following families with familial hypercholesterolaemia, a genetic condition that, in 90% of cases causes coronary artery disease (FRAMINGHAM study) and in 60% of cases may lead to an early death;[14] they had identified a mutation on chromosome 1 carried by some of these families, but had been unable to identify the relevant gene. The labs got together and by the end of the year published their work, linking mutations in the gene, now identified as PCSK9, to the condition.[15][13] In their paper, they speculated that the mutations might make the gene overactive. In that same year, investigators at Rockefeller University and University of Texas Southwestern had discovered the same protein in mice, and had worked out the novel pathway that regulates LDL cholesterol in which PCSK9 is involved, and it soon became clear that the mutations identified in France led to excessive PCSK9 activity, and thus excessive removal of the LDL receptor, leaving people carrying the mutations with too much LDL cholesterol.[13] Meanwhile, Dr. Helen H. Hobbs and Dr. Jonathan Cohen at UT-Southwestern had been studying people with very high and very low cholesterol, and had been collecting DNA samples.[16] With the new knowledge about the role of PCSK9 and its location in the genome, they sequenced the relevant region of chromosome 1 in people with very low cholesterol and they found nonsense mutations in the gene, thus validating PCSK9 as a biological target for drug discovery.[13][17]
In July 2015, the FDA approved the first PCSK9 Inhibitor drugs for medical use.[18]
# Structure
## Gene
The PCSK9 gene resides on chromosome 1 at the band 1p32.3[19] and includes 13 exons.[20] This gene produces two isoforms through alternative splicing.[21]
## Protein
PCSK9 is a member of the peptidase S8 family.[21]
The solved structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1-30); the N-terminal prodomain (residues 31-152); the catalytic domain (residues 153-425); and the C-terminal domain (residues 426-692), which is further divided into three modules.[22] The N-terminal prodomain has a flexible crystal structure and is responsible for regulating PCSK9 function by interacting with and blocking the catalytic domain, which otherwise binds the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR.[22][23][24] While previous studies indicated that the C-terminal domain was uninvolved in binding LDLR,[25][26] a recent study by Du et al. demonstrated that the C-terminal domain does bind LDLR.[22] The secretion of PCSK9 is largely dependent on the autocleavage of the signal peptide and N-terminal prodomain, though the N-terminal prodomain retains its association with the catalytic domain. In particular, residues 61-70 in the N-terminal prodomain are crucial for its autoprocessing.[22]
# Function
## Role and regulatory function
This protein plays a major regulatory role in cholesterol homeostasis, mainly by reducing LDLR levels on the plasma membrane. Reduced LDLR levels result in decreased metabolism of LDL-particles, which could lead to hypercholesterolemia.[29] When LDL binds to LDLR, it induces internalization of LDLR-LDL complex within an endosome. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation.[30] The conformational change causes LDLR to release its LDL ligand, and the receptor is recycled back to the plasma membrane. However, when PCSK9 binds to the LDLR (through the EGF-A domain), PCSK9 prevents the conformational change of the receptor-ligand complex. This inhibition redirects the LDLR to the lysosome instead.[30]
PCSK9 is synthesized as a soluble zymogen that undergoes autocatalytic intramolecular processing in the endoplasmic reticulum. The protein may function as a proprotein convertase.[3] PCSK9 is expressed mainly in the liver, the intestine, the kidney, and the central nervous system.[31] PCSK9 also plays an important role in intestinal triglyceride-rich apoB lipoprotein production in small intestine and postprandial lipemia.[32][33][34]
After being processed in the ER, PCSK9 co-localizes with the protein sortilin on its way through the Golgi and trans-Golgi complex. A PCSK9-sortilin interaction is proposed to be required for cellular secretion of PCSK9.[35] In healthy humans, plasma PCSK9 levels directly correlate with plasma sortilin levels, following a diurnal rhythm similar to cholesterol synthesis.[36][37] The plasma PCSK9 concentration is higher in women compared to men, and the PCSK9 concentrations decrease with age in men but increase in women, suggesting that estrogen level most likely plays a role.[38][39] PCSK9 gene expression can be regulated by sterol-response element binding proteins (SREBP-1/2), which also controls LDLR expression.[36]
PCSK9 may also have a role in the differentiation of cortical neurons.[1]
## Clinical significance
Variants of PCSK9 can reduce or increase circulating cholesterol. LDL-particles are removed from the blood when they bind to LDLR on the surface of cells, including liver cells, and are taken inside the cells. When PCSK9 binds to an LDLR, the receptor is destroyed along with the LDL particle. PCSK9 degrades LDLR by preventing the hairpin conformational change of LDLR.[40] If PCSK9 does not bind, the receptor will return to the surface of the cell and can continue to remove LDL-particles from the bloodstream.[41]
Other variants are associated with a rare autosomal dominant familial hypercholesterolemia (HCHOLA3).[42][15][43] The mutations increase its protease activity, reducing LDLR levels and preventing the uptake of cholesterol into the cells.[15]
In humans, PCSK9 was initially discovered as a protein expressed in the brain.[44] However, it has also been described in the kidney, the pancreas, liver and small intestine.[44] Recent evidence indicate that PCSK9 is highly expressed in arterial walls such as endothelium, smooth muscle cells, and macrophages, with a local effect that can regulate vascular homeostasis and atherosclerosis.[45][46][47] Accordingly, it is now very clear that PCSK9 has pro-atherosclerotic effects and regulates lipoprotein synthesis.[48]
As PCSK9 binds to LDLR, which prevents the removal of LDL-particles from the blood plasma, several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).[9][44][49][50][51][52][53][54] Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[48][55][56]
In addition to its lipoprotein synthetic and pro-atherosclerotic effects, PCSK9 is involved in glucose metabolism and obesity,[57] regulation of re-absorption of sodium in the kidney which is relevant in hypertension.[58][59] Furthermore, PCSK9 may be involved in bacterial or viral infections and sepsis.[60][61] In the brain the role of PCSK9 is still controversial and may be either pro-apoptotic or protective in the development of the nervous system.[1] PCSK9 levels have been detected in the cerebrospinal fluid at a 50-60 times lower level than in serum.[62]
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci including the PCSK9 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[4]
# PCSK9 Inhibitor Drugs
Several studies have determined the potential use of PCSK9 inhibitors in the treatment of hyperlipoproteinemia (commonly called hypercholesterolemia).[9][44] Furthermore, loss-of-function mutations in the PCSK9 gene result in lower levels of LDL and protection against cardiovascular disease.[48]
PCSK9 inhibitor drugs are now approved by the FDA to treat familial hypercholesterolemia.[10]
## As a drug target
Drugs can inhibit PCSK9, leading to lowered circulating LDL particle concentrations. Since LDL particle concentrations are thought by many experts to be a driver of cardiovascular disease like heart attacks, it is plausible that these drugs may also reduce the risk of such diseases. Clinical studies, including phase III clinical trials, are now underway to describe the effect of PCSK9 inhibition on cardiovascular disease, and the safety and efficacy profile of the drugs.[63][64][65][66][67] Among those inhibitors under development in December 2013 were the antibodies alirocumab, evolocumab, 1D05-IgG2 (Merck), RG-7652 and LY3015014, as well as the RNAi therapeutic inclisiran.[68] PCSK9 inhibitors are promising therapeutics for the treatment of people who exhibit statin intolerance, or as a way to bypass frequent dosage of statins for higher LDL concentration reduction.[69][70]
A review published in 2015 concluded that these agents, when used in patients with high LDL-particle concentrations (thus at greatly elevated risk for cardiovascular disease) seem to be safe and effective at reducing all-cause mortality, cardiovascular mortality, and heart attacks.[71] However more recent reviews conclude that while PCSK9 inhibitor treatment provides additional benefits beyond maximally tolerated statin therapy in high-risk individuals,[72] PCSK9 inhibitor use probably results in little or no difference in mortality.[73]
Regeneron (in collaboration with Sanofi) became the first to market a PCSK9 inhibitor, with a competitor Amgen reaching market slightly later.[10] The drugs are approved by the FDA for treatment of hypercholesterolemia, notably the genetic condition heterozygous familial hypercholesterolemia which causes high cholesterol levels and heart attacks at a young age.
### Warning
An FDA warning in March 2014 about possible cognitive adverse effects of PCSK9 inhibition caused concern, as the FDA asked companies to include neurocognitive testing into their Phase III clinical trials.[74]
## Monoclonal antibodies
A number of monoclonal antibodies that bind to and inhibit PCSK9 near the catalytic domain were in clinical trials as of 2014[update]. These include evolocumab (Amgen), bococizumab (Pfizer), and alirocumab (Aventis/Regeneron).[75] As of July 2015[update], the EU approved these drugs including Evolocumab/Amgen according to Medscape news agency report. A meta-analysis of 24 clinical trials has shown that monoclonal antibodies against PCSK9 can reduce cholesterol, cardiac events and all-cause mortality.[71]
A possible side effect of the monoclonal antibody might be irritation at the injection site. Before the infusions, participants received oral corticosteroids, histamine receptor blockers, and acetaminophen to reduce the risk of infusion-related reactions, which by themselves will cause several side effects.[76]
## Peptide mimics
Peptides that mimick the EGFA domain of the LDLR that binds to PCSK9 have been developed to inhibit PCSK9.[77]
## Gene silencing
The PCSK9 antisense oligonucleotide increases expression of the LDLR and decreases circulating total cholesterol levels in mice.[78] A locked nucleic acid reduced PCSK9 mRNA levels in mice.[79][80] Initial clinical trials showed positive results of ALN-PCS, which acts by means of RNA interference.[67][81][82]
## Vaccination
A vaccine that targets PCSK9 has been developed to treat high LDL-particle concentrations. The vaccine uses a VLP (virus-like particle) as an immunogenic carrier of an antigenic PCSK9 peptide. VLP's are viruses that have had their DNA removed so that they retain their external structure for antigen display but are unable to replicate; they can induce an immune response without causing infection. Mice and macaques vaccinated with bacteriophage VLPs displaying PCSK9-derived peptides developed high-titer IgG antibodies that bound to circulating PCSK9. Vaccination was associated with significant reductions in total cholesterol, free cholesterol, phospholipids, and triglycerides.[83]
## Naturally occurring inhibitors
The plant alkaloid berberine inhibits the transcription of the PCSK9 gene in immortalized human hepatocytes in vitro,[84] and lowers serum PCSK9 in mice and hamsters in vivo.[85] It has been speculated[85] that this action contributes to the ability of berberine to lower serum cholesterol.[86] Annexin A2, an endogenous protein, is a natural inhibitor of PCSK9 activity.[87] | https://www.wikidoc.org/index.php/PCSK9 | |
589fd97806a8edb9dfc28f0f469bc66f1f04254d | wikidoc | PD-L1 | PD-L1
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif . This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.
# History
PD-L1 was characterized at the Mayo Clinic as an immune regulatory molecule, B7-H1. Later this molecule was renamed as PD-L1 because it was identified as a ligand of PD-1 Several human cancer cells expressed high levels of B7-H1, and blockade of B7-H1 reduced the growth of tumors in the presence of immune cells. At that time it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity. In 2003 B7-H1 was shown to be expressed on Myeloid cells as checkpoint protein and was proposed as potential target in cancer immunotherapy in human clinic
# Binding
PD-L1 binds to its receptor, PD-1, found on activated T cells, B cells, and myeloid cells, to modulate activation or inhibition. The affinity between PD-L1 and PD-1, as defined by the dissociation constant Kd, is 770nM. PD-L1 also has an appreciable affinity for the costimulatory molecule CD80 (B7-1), but not CD86 (B7-2). CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for CD28 and CTLA-4 (4.0µM and 400nM, respectively). The related molecule PD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140nM).
Said et al. showed that PD-1, up-regulated on activated CD4 T-cells, can bind to PD-L1 expressed on monocytes and induces IL-10 production by the latter.
# Signaling
Engagement of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with CD3ζ. PD-1 signaling attenuates PKC-θ activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors NF-κB and AP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation to naive T cells, by inducing the up-regulation of the E3 ubiquitin ligase CBL-b.
# Regulation
## By interferons
Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells. The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor. Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.
## On macrophages
PD-L1 is notably expressed on macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and interferon-gamma) greatly upregulate PD-L1. Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon-gamma, but is not at all responsible for its constitutive expression before activation in these mice.
## Role of microRNAs
Resting human cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by microRNA miR-513. Upon treatment with interferon-gamma, miR-513 was down-regulated, thereby lifting suppression of PD-L1 protein. In this way, interferon-gamma can induce PD-L1 protein expression by inhibiting gene-mediated suppression of mRNA translation.
## Epigenetic regulation
PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.
# Clinical significance
## Cancer
It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.
Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials. Clinically available examples include Durvalumab, atezolizumab and avelumab.
In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1.
### Measurement
There are two scoring systems to measure the presence of PD-L1 expression in tumors.
- PD-L1 tumor proportion score (TPS). TPS is The proportion of PD-L1 stained tumor cells divided by the total number of viable tumor cells X 100
\frac{\text{Number of PD-L1 stained tumor cells}}{\text{Total number of viable tumor cells}}\star\text{100}
- PD-L1 combined positive score (CPS). CPS is The proportion of PD-L1 stained tumor cells, and immune cells, divided by the total number of viable tumor cells X 100
\frac{\text{Number of PD-L1 stained tumor cells }\mathit{and}\text{ immune cells}}{\text{Total number of viable tumor cells}}\star\text{100}
Cutoff for positive for both scores is 1%
CPS positive is much more common and may occur on four-fold as many patients as TPS positive.
## Listeria monocytogenes
In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells). This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
## Autoimmunity
The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).
In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus (SLE). Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5-day time course, expressing this protein only during disease remissions. This may be one mechanism whereby peripheral tolerance is lost in SLE. | PD-L1
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.[1]
Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that has been speculated to play a major role in suppressing the adaptive arm of immune system during particular events such as pregnancy, tissue allografts, autoimmune disease and other disease states such as hepatitis. Normally the adaptive immune system reacts to antigens that are associated with immune system activation by exogenous or endogenous danger signals. In turn, clonal expansion of antigen-specific CD8+ T cells and/or CD4+ helper cells is propagated. The binding of PD-L1 to the inhibitory checkpoint molecule PD-1 transmits an inhibitory signal based on interaction with phosphatases (SHP-1 or SHP-2) via Immunoreceptor Tyrosine-Based Switch Motif (ITSM) motif [2]. This reduces the proliferation of antigen-specific T-cells in lymph nodes, while simultaneously reducing apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells) - further mediated by a lower regulation of the gene Bcl-2.
# History
PD-L1 was characterized at the Mayo Clinic as an immune regulatory molecule, B7-H1. Later this molecule was renamed as PD-L1 because it was identified as a ligand of PD-1[3] Several human cancer cells expressed high levels of B7-H1, and blockade of B7-H1 reduced the growth of tumors in the presence of immune cells. At that time it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity.[4] In 2003 B7-H1 was shown to be expressed on Myeloid cells as checkpoint protein and was proposed as potential target in cancer immunotherapy in human clinic [5]
# Binding
PD-L1 binds to its receptor, PD-1, found on activated T cells, B cells, and myeloid cells, to modulate activation or inhibition. The affinity between PD-L1 and PD-1, as defined by the dissociation constant Kd, is 770nM. PD-L1 also has an appreciable affinity for the costimulatory molecule CD80 (B7-1), but not CD86 (B7-2).[6] CD80's affinity for PD-L1, 1.4µM, is intermediate between its affinities for CD28 and CTLA-4 (4.0µM and 400nM, respectively). The related molecule PD-L2 has no such affinity for CD80 or CD86, but shares PD-1 as a receptor (with a stronger Kd of 140nM).
Said et al. showed that PD-1, up-regulated on activated CD4 T-cells, can bind to PD-L1 expressed on monocytes and induces IL-10 production by the latter.[7]
# Signaling
Engagement of PD-L1 with its receptor PD-1 on T cells delivers a signal that inhibits TCR-mediated activation of IL-2 production and T cell proliferation. The mechanism involves inhibition of ZAP70 phosphorylation and its association with CD3ζ.[8] PD-1 signaling attenuates PKC-θ activation loop phosphorylation (resulting from TCR signaling), necessary for the activation of transcription factors NF-κB and AP-1, and for production of IL-2. PD-L1 binding to PD-1 also contributes to ligand-induced TCR down-modulation during antigen presentation to naive T cells, by inducing the up-regulation of the E3 ubiquitin ligase CBL-b.[9]
# Regulation
## By interferons
Upon IFN-γ stimulation, PD-L1 is expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells.[10] The PD-L1 gene promoter region has a response element to IRF-1, the interferon regulatory factor.[11] Type I interferons can also upregulate PD-L1 on murine hepatocytes, monocytes, DCs, and tumor cells.[12]
## On macrophages
PD-L1 is notably expressed on macrophages. In the mouse, it has been shown that classically activated macrophages (induced by type I helper T cells or a combination of LPS and interferon-gamma) greatly upregulate PD-L1.[13] Alternatively, macrophages activated by IL-4 (alternative macrophages), slightly upregulate PD-L1, while greatly upregulating PD-L2. It has been shown by STAT1-deficient knock-out mice that STAT1 is mostly responsible for upregulation of PD-L1 on macrophages by LPS or interferon-gamma, but is not at all responsible for its constitutive expression before activation in these mice.
## Role of microRNAs
Resting human cholangiocytes express PD-L1 mRNA, but not the protein, due to translational suppression by microRNA miR-513.[14] Upon treatment with interferon-gamma, miR-513 was down-regulated, thereby lifting suppression of PD-L1 protein. In this way, interferon-gamma can induce PD-L1 protein expression by inhibiting gene-mediated suppression of mRNA translation.
## Epigenetic regulation
PD-L1 promoter DNA methylation may predict survival in some cancers after surgery.[15]
# Clinical significance
## Cancer
It appears that upregulation of PD-L1 may allow cancers to evade the host immune system. An analysis of 196 tumor specimens from patients with renal cell carcinoma found that high tumor expression of PD-L1 was associated with increased tumor aggressiveness and a 4.5-fold increased risk of death.[16]
Many PD-L1 inhibitors are in development as immuno-oncology therapies and are showing good results in clinical trials.[17] Clinically available examples include Durvalumab, atezolizumab and avelumab.[18]
In normal tissue, feedback between transcription factors like STAT3 and NF-κB restricts the immune response to protect host tissue and limit inflammation. In cancer, loss of feedback restriction between transcription factors can lead to increased local PD-L1 expression, which could limit the effectiveness of systemic treatment with agents targeting PD-L1.
[19]
### Measurement
There are two scoring systems to measure the presence of PD-L1 expression in tumors[20].
- PD-L1 tumor proportion score (TPS). TPS is The proportion of PD-L1 stained tumor cells divided by the total number of viable tumor cells X 100
<math>\frac{\text{Number of PD-L1 stained tumor cells}}{\text{Total number of viable tumor cells}}\star\text{100}</math>
- PD-L1 combined positive score (CPS). CPS is The proportion of PD-L1 stained tumor cells, and immune cells, divided by the total number of viable tumor cells X 100
<math>\frac{\text{Number of PD-L1 stained tumor cells }\mathit{and}\text{ immune cells}}{\text{Total number of viable tumor cells}}\star\text{100}</math>
Cutoff for positive for both scores is 1%
CPS positive is much more common and may occur on four-fold as many patients as TPS positive[20].
## Listeria monocytogenes
In a mouse model of intracellular infection, L. monocytogenes induced PD-L1 protein expression in T cells, NK cells, and macrophages. PD-L1 blockade (using blocking antibodies) resulted in increased mortality for infected mice. Blockade reduced TNFα and nitric oxide production by macrophages, reduced granzyme B production by NK cells, and decreased proliferation of L. monocytogenes antigen-specific CD8 T cells (but not CD4 T cells).[21] This evidence suggests that PD-L1 acts as a positive costimulatory molecule in intracellular infection.
## Autoimmunity
The PD-1/PD-L1 interaction is implicated in autoimmunity from several lines of evidence. NOD mice, an animal model for autoimmunity that exhibit a susceptibility to spontaneous development of type I diabetes and other autoimmune diseases, have been shown to develop precipitated onset of diabetes from blockade of PD-1 or PD-L1 (but not PD-L2).[22]
In humans, PD-L1 was found to have altered expression in pediatric patients with Systemic lupus erythematosus (SLE). Studying isolated PBMC from healthy children, immature myeloid dendritic cells and monocytes expressed little PD-L1 at initial isolation, but spontaneously up-regulated PD-L1 by 24 hours. In contrast, both mDC and monocytes from patients with active SLE failed to upregulate PD-L1 over a 5-day time course, expressing this protein only during disease remissions.[23] This may be one mechanism whereby peripheral tolerance is lost in SLE. | https://www.wikidoc.org/index.php/PD-L1 | |
3b864699ec6a17862b016997fdbec674be68b83b | wikidoc | PDCD2 | PDCD2
Programmed cell death protein 2 is a protein that in humans is encoded by the PDCD2 gene.
# Function
This gene encodes a nuclear protein expressed in a variety of tissues. The rat homolog, Rp8, is transiently expressed in immature thymocytes and is thought to be involved in programmed cell death. Expression of the human gene has been shown to be repressed by BCL6, a transcriptional repressor required for lymph node germinal center development, suggesting that BCL6 regulates apoptosis by its effects on PDCD2. This gene is closely linked on chromosome 6 to the gene for TBP, the TATA binding protein. Six transcripts encoding different proteins have been identified.
# Interactions
PDCD2 has been shown to interact with Host cell factor C1 and Parkin (ligase).
# Model organisms
Model organisms have been used in the study of PDCD2 function. A conditional knockout mouse line called Pdcd2tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | PDCD2
Programmed cell death protein 2 is a protein that in humans is encoded by the PDCD2 gene.[1][2]
# Function
This gene encodes a nuclear protein expressed in a variety of tissues. The rat homolog, Rp8, is transiently expressed in immature thymocytes and is thought to be involved in programmed cell death. Expression of the human gene has been shown to be repressed by BCL6, a transcriptional repressor required for lymph node germinal center development, suggesting that BCL6 regulates apoptosis by its effects on PDCD2. This gene is closely linked on chromosome 6 to the gene for TBP, the TATA binding protein. Six transcripts encoding different proteins have been identified.[2]
# Interactions
PDCD2 has been shown to interact with Host cell factor C1[3] and Parkin (ligase).[4]
# Model organisms
Model organisms have been used in the study of PDCD2 function. A conditional knockout mouse line called Pdcd2tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[5] Male and female animals underwent a standardized phenotypic screen[6] to determine the effects of deletion.[7][8][9][10] Additional screens performed: - In-depth immunological phenotyping[11] | https://www.wikidoc.org/index.php/PDCD2 | |
93e6cbe6d9b21f500b51fbbf09518a95742d6176 | wikidoc | PDCD4 | PDCD4
Programmed cell death protein 4 is a protein that in humans is encoded by the PDCD4 gene. It is one of the targets of an oncomiR, MIRN21.
# Function
This gene encodes a protein localized to the nucleus in proliferating cells. Expression of this gene is modulated by cytokines in natural killer and T cells. The gene product is thought to play a role in apoptosis but the specific role has not yet been determined. Two transcripts encoding different isoforms have been identified.
# Interactions
PDCD4 has been shown to interact with RPS13 and Ribosomal protein L5. | PDCD4
Programmed cell death protein 4 is a protein that in humans is encoded by the PDCD4 gene.[1][2] It is one of the targets of an oncomiR, MIRN21.[3]
# Function
This gene encodes a protein localized to the nucleus in proliferating cells. Expression of this gene is modulated by cytokines in natural killer and T cells. The gene product is thought to play a role in apoptosis but the specific role has not yet been determined. Two transcripts encoding different isoforms have been identified.[2]
# Interactions
PDCD4 has been shown to interact with RPS13[4] and Ribosomal protein L5.[4] | https://www.wikidoc.org/index.php/PDCD4 | |
1ce5edd895f9935554dc5af3e8fcf2c98cbc8629 | wikidoc | PDCD6 | PDCD6
Programmed cell death protein 6 is a protein that in humans is encoded by the PDCD6 gene.
This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant.
# Interactions
PDCD6 has been shown to interact with ASK1, PDCD6IP, Fas receptor, ANXA11 and PEF1. | PDCD6
Programmed cell death protein 6 is a protein that in humans is encoded by the PDCD6 gene.[1]
This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant.[2]
# Interactions
PDCD6 has been shown to interact with ASK1,[3] PDCD6IP,[4][5] Fas receptor,[6] ANXA11[5] and PEF1.[7] | https://www.wikidoc.org/index.php/PDCD6 | |
53791c74c51b9d2a50a43670d0e841b6056f3340 | wikidoc | PDE4A | PDE4A
cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.
# Function
The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the secondary messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes. Recently, it has been shown through the use of PDE4A knock out mice that PDE4A may play a role in the regulation of anxiety and emotional memory.
# Clinical significance
PDE4A is a target of a number of drugs including:
- rolipram (antidepressant and antiinflammatory) and cilomilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, 6, and 7
- roflumilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, and 6 | PDE4A
cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.[1][2]
# Function
The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the secondary messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes.[2] Recently, it has been shown through the use of PDE4A knock out mice that PDE4A may play a role in the regulation of anxiety and emotional memory.[3]
# Clinical significance
PDE4A is a target of a number of drugs including:[4][5][6]
- rolipram (antidepressant and antiinflammatory) and cilomilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, 6, and 7
- roflumilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, and 6 | https://www.wikidoc.org/index.php/PDE4A | |
c4ec28bfbec7889e4cddc8543731b6adbf0610fb | wikidoc | PDE4B | PDE4B
cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.
This gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. The cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. This gene encodes a protein that specifically hydrolyzes cAMP. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
# Clinical relevance
Altered activity of this protein has been associated with schizophrenia and bipolar disorder. PDE4B is believed to be the PDE4 subtype involved in the antipsychotic effects of PDE4 inhibitors such as rolipram. PDE4B is involved in dopamine-associated and stress-related behaviours. It has also recently been found to modulate cognition, as reduction in PDE4B activity improves memory and long-term plasticity in mouse models, possibly supporting further therapeutic applications.
# Inhibitors
AN2728, a boron-containing drug candidate that as of 2015 was under development by Anacor Pharmaceuticals for the topical treatment of psoriasis and atopic dermatitis (atopic eczema). mainly acting on PDE4B. | PDE4B
cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.[1]
This gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. The cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. This gene encodes a protein that specifically hydrolyzes cAMP. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[1][2]
# Clinical relevance
Altered activity of this protein has been associated with schizophrenia and bipolar disorder.[1] PDE4B is believed to be the PDE4 subtype involved in the antipsychotic effects of PDE4 inhibitors such as rolipram.[3] PDE4B is involved in dopamine-associated and stress-related behaviours.[4] It has also recently been found to modulate cognition, as reduction in PDE4B activity improves memory and long-term plasticity in mouse models, possibly supporting further therapeutic applications.[5]
# Inhibitors
AN2728, a boron-containing drug candidate that as of 2015 was under development by Anacor Pharmaceuticals for the topical treatment of psoriasis and atopic dermatitis (atopic eczema).[6][7][8] mainly acting on PDE4B.[8] | https://www.wikidoc.org/index.php/PDE4B | |
a825bfbb4fdb00a5437540f62e6561a59b6b04bd | wikidoc | PDE4D | PDE4D
cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.
# Function
The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the second messenger cAMP, which is a key signal transduction molecule in multiple cell types, including vascular cells (Dominiczak and McBride, 2003).
# Interactions
PDE4D has been shown to interact with myomegalin and GNB2L1.
# Clinical relevance
Mutations in this gene have been associated to cases of acrodysostosis.
This is the subtype of PDE4 that appears to be involved in the emetic and antidepressant effects of PDE4 inhibitors.
Furthermore, changes in expression of the isoform PDE4D7 have been proposed as prostate cancer biomarker. | PDE4D
cAMP-specific 3',5'-cyclic phosphodiesterase 4D is an enzyme that in humans is encoded by the PDE4D gene.
# Function
The PDE4D gene is complex and has at least 9 different isoforms that encode functional proteins. These proteins degrade the second messenger cAMP, which is a key signal transduction molecule in multiple cell types, including vascular cells (Dominiczak and McBride, 2003).[supplied by OMIM][1]
# Interactions
PDE4D has been shown to interact with myomegalin[2] and GNB2L1.[3][4]
# Clinical relevance
Mutations in this gene have been associated to cases of acrodysostosis.[5]
This is the subtype of PDE4 that appears to be involved in the emetic and antidepressant effects of PDE4 inhibitors.[6]
Furthermore, changes in expression of the isoform PDE4D7 have been proposed as prostate cancer biomarker.
[7]
[8]
[9] | https://www.wikidoc.org/index.php/PDE4D | |
db651f501119de25f799e19cea0d69f036f14367 | wikidoc | PDE6B | PDE6B
Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta is the beta subunit of the protein complex PDE6 that is encoded by the PDE6B gene. PDE6 is crucial in transmission and amplification of visual signal. The existence of this beta subunit is essential for normal PDE6 functioning. Mutations in this subunit are responsible for retinal degeneration such as retinitis pigmentosa or congenital stationary night blindness.
# Structure
PDE6 is a protein complex located on the photoreceptor's outer segment, and plays an important role in the phototransduction cascade. There are two types of photoreceptors: cones and rods. The rod and cone PDE6 complexes have different structures. PDE6β together with PDE6α and two identical inhibitory subunits, PDE6γ, form the rod PDE6 holoenzyme while the cone PDE6 complex only consists of two identical PDE6α' catalytic subunits. PDE6β, one of the catalytic units in rod PDE6, is composed of three domains: two N-terminal GAF domains and one C-terminal catalytic domain.The non-catalytic GAF domains are responsible for cGMP binding. The C-terminal interacts with cell membrane by isoprenylation and S-carboxylmethylation.
# Function
Absorption of photons by rhodopsin triggers a signal transduction cascade in rod photoreceptors. This phototransduction cascade leads to hydrolysis of cGMP by cGMP-phosphodiesterase (PDE) that closes cGMP-gated channels and hyperpolarizes the cell. PDE6β is necessary for the formation of a functional phosphodiesterase holoenzyme.
## Function of PDE6
PDE6 is a highly concentrated protein in retinal photoreceptors. With the presence of the GAF domain, PDE6 can actively bind to the cGMP. The inactive PDE6 in the dark allows cGMP to bind to cGMP gated ion channels. The channel remains open as long as cGMP is binding to it, which allows constant electron flow in to the photoreceptor cell through the plasma membrane. Light causes the visual pigment, rhodopsin, to activate. This process leads to the release of subunit PDE6γ from PDE6αβ, activating PDE6 which leads to the hydrolysis of cGMP. Without the cGMP binding, the ion channel closes, leading to the hyperpolarization. After hyperpolarization the presnaptic transmitter is reduced. Next, the enzyme guanylate cyclase restores cGMP, which reopens the membrane channels. This process is called light adaptation.
## Function of PDE6B
PDE6β is the only protein that undergoes the two types of post-translational modification, prenylation and carboxymethylation. The geranylgeranyl group of PDE6B is the result of these modifications, which are responsible for the rod PDE6's interaction with membrane.
# Animal studies
## rd1 mouse
Mutation of the PDE6b gene leads to the dysfunction of PDE, which results in failure of hydrolysis of cGMP. The rd1 mouse is a well-characterized animal model of retinitis pigmentosa caused by the mutation of Pde6b gene. The phenotype was first discovered in rodless mice in the 1920s by Keeler. An insertion of Murine leukemia provirus is present near the first exon combined with a point mutation, which introduces a stop codon in exon 7. In addition to the rd1 mouse, a missense mutation (R560C) in exon 13 of the Pde6b gene is the character of another animal model of recessive retinal degeneration.
In rd1 animals, the retinal rod photoreceptor cells begin degenerating at about postnatal day 10, and by 3 weeks no rod photoreceptors remain. Degeneration is preceded by accumulation of cGMP in the retina and is correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase. Cone photoreceptors undergo a slower degeneration over the course of a year, which causes the mutants to completely go blind. The possibility of altering the course of retinal degeneration through subretinal injection of recombinant replication defective adenovirus that contained the murine cDNA for wildtype PDE6β was tested in rd1 mice. Subretinal injection of rd1 mice was carried out 4 days after birth, before the onset of rod photoreceptor degeneration. Following therapy, Pde6β transcripts and enzyme activity were detected, and histologic studies revealed that photoreceptor cell death was significantly retarded.
The albino FVB mouse laboratory strain become blind by weaning age due to a mutant allele of the PDE6b gene. There are pigmented derivative strains of FVB that lack this trait.
## rcd1 dog
Similar to rd1 in mice, Rod-cone dysplasia type 1 (rcd1-PRA) is a form of progressive retinal atrophy (PRA), with early onset of the disease. The Irish Setter is a characterized animal model of rcd1. The mutation is caused by a nonsense mutation in pde6b gene. Photoreceptors start degeneration at postnatal day 13 until a year after the dog is totally blind. | PDE6B
Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta is the beta subunit of the protein complex PDE6 that is encoded by the PDE6B gene.[1][2] PDE6 is crucial in transmission and amplification of visual signal. The existence of this beta subunit is essential for normal PDE6 functioning. Mutations in this subunit are responsible for retinal degeneration such as retinitis pigmentosa[3][4] or congenital stationary night blindness.[5]
# Structure
PDE6 is a protein complex located on the photoreceptor's outer segment, and plays an important role in the phototransduction cascade.[6] There are two types of photoreceptors: cones and rods. The rod and cone PDE6 complexes have different structures. PDE6β together with PDE6α and two identical inhibitory subunits, PDE6γ, form the rod PDE6 holoenzyme while the cone PDE6 complex only consists of two identical PDE6α' catalytic subunits.[7] PDE6β, one of the catalytic units in rod PDE6, is composed of three domains: two N-terminal GAF domains and one C-terminal catalytic domain.The non-catalytic GAF domains are responsible for cGMP binding. The C-terminal interacts with cell membrane by isoprenylation and S-carboxylmethylation.[7]
# Function
Absorption of photons by rhodopsin triggers a signal transduction cascade in rod photoreceptors. This phototransduction cascade leads to hydrolysis of cGMP by cGMP-phosphodiesterase (PDE) that closes cGMP-gated channels and hyperpolarizes the cell.[8] PDE6β is necessary for the formation of a functional phosphodiesterase holoenzyme.[7]
## Function of PDE6
PDE6 is a highly concentrated protein in retinal photoreceptors. With the presence of the GAF domain, PDE6 can actively bind to the cGMP. The inactive PDE6 in the dark allows cGMP to bind to cGMP gated ion channels. The channel remains open as long as cGMP is binding to it, which allows constant electron flow in to the photoreceptor cell through the plasma membrane. Light causes the visual pigment, rhodopsin, to activate. This process leads to the release of subunit PDE6γ from PDE6αβ, activating PDE6 which leads to the hydrolysis of cGMP. Without the cGMP binding, the ion channel closes, leading to the hyperpolarization.[7] After hyperpolarization the presnaptic transmitter is reduced. Next, the enzyme guanylate cyclase restores cGMP, which reopens the membrane channels. This process is called light adaptation.
## Function of PDE6B
PDE6β is the only protein that undergoes the two types of post-translational modification, prenylation and carboxymethylation.[9] The geranylgeranyl group of PDE6B is the result of these modifications, which are responsible for the rod PDE6's interaction with membrane.
# Animal studies
## rd1 mouse
Mutation of the PDE6b gene leads to the dysfunction of PDE, which results in failure of hydrolysis of cGMP. The rd1 mouse is a well-characterized animal model of retinitis pigmentosa caused by the mutation of Pde6b gene.[10] The phenotype was first discovered in rodless mice in the 1920s by Keeler.[11] An insertion of Murine leukemia provirus is present near the first exon combined with a point mutation, which introduces a stop codon in exon 7. In addition to the rd1 mouse, a missense mutation (R560C) in exon 13 of the Pde6b gene is the character of another animal model of recessive retinal degeneration.
In rd1 animals, the retinal rod photoreceptor cells begin degenerating at about postnatal day 10, and by 3 weeks no rod photoreceptors remain. Degeneration is preceded by accumulation of cGMP in the retina and is correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase.[10][12] Cone photoreceptors undergo a slower degeneration over the course of a year, which causes the mutants to completely go blind.[13] The possibility of altering the course of retinal degeneration through subretinal injection of recombinant replication defective adenovirus that contained the murine cDNA for wildtype PDE6β was tested in rd1 mice.[14] Subretinal injection of rd1 mice was carried out 4 days after birth, before the onset of rod photoreceptor degeneration. Following therapy, Pde6β transcripts and enzyme activity were detected, and histologic studies revealed that photoreceptor cell death was significantly retarded.[2]
The albino FVB mouse laboratory strain become blind by weaning age due to a mutant allele of the PDE6b gene. There are pigmented derivative strains of FVB that lack this trait.
## rcd1 dog
Similar to rd1 in mice, Rod-cone dysplasia type 1 (rcd1-PRA) is a form of progressive retinal atrophy (PRA), with early onset of the disease. The Irish Setter is a characterized animal model of rcd1. The mutation is caused by a nonsense mutation in pde6b gene. Photoreceptors start degeneration at postnatal day 13 until a year after the dog is totally blind.[15] | https://www.wikidoc.org/index.php/PDE6B | |
1fb83f7124f847826dd7a270306d3e9e1d5388d4 | wikidoc | PDGFB | PDGFB
Platelet-derived growth factor subunit B is a protein that in humans is encoded by the PDGFB gene.
# Function
The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a motif of eight cysteines. This gene product can exist either as a homodimer (PDGF-BB) or as a heterodimer with the platelet-derived growth factor alpha (PDGFA) polypeptide (PDGF-AB), where the dimers are connected by disulfide bonds.
# Clinical significance
Mutations in this gene are associated with meningioma. Reciprocal translocations between chromosomes 22 and 17, at sites where this gene and that for COL1A1 are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans resulting from unregulated expression of growth factor. Two splice variants have been identified for this gene. | PDGFB
Platelet-derived growth factor subunit B is a protein that in humans is encoded by the PDGFB gene.[1][2]
# Function
The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a motif of eight cysteines. This gene product can exist either as a homodimer (PDGF-BB) or as a heterodimer with the platelet-derived growth factor alpha (PDGFA) polypeptide (PDGF-AB), where the dimers are connected by disulfide bonds.
# Clinical significance
Mutations in this gene are associated with meningioma. Reciprocal translocations between chromosomes 22 and 17, at sites where this gene and that for COL1A1 are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans resulting from unregulated expression of growth factor. Two splice variants have been identified for this gene.[3] | https://www.wikidoc.org/index.php/PDGFB | |
915984c65377701f1f561de7da469b2a27e01f02 | wikidoc | PDGFC | PDGFC
Platelet-derived growth factor C, also known as PDGF-C, is a 345-amino acid protein that in humans is encoded by the PDGFC gene. Platelet-derived growth factors are important in connective tissue growth, survival and function, and consist of disulphide-linked dimers involving two polypeptide chains, PDGF-A and PDGF-B. PDGF-C is a member of the PDGF/VEGF family of growth factors with a unique two-domain structure and expression pattern. PDGF-C was not previously identified with PDGF-A and PDGF-B, possibly because it may be that it is synthesized and secreted as a latent growth factor, requiring proteolytic removal of the N-terminal CUB domain for receptor binding and activation.
# Function
The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a core motif of eight cysteines. This gene product appears to form only homodimers. It differs from the platelet-derived growth factor alpha and beta polypeptides in having an unusual N-terminal domain, the CUB domain.
PDGF-C is a key component of the PDGFR-α signaling pathway and has a specific role in palatogenesis and the morphogenesis of the integumentary tissue. The phenotypes of compound mutants imply that PDGF-C and PDGF-A may function as principal ligands for PDGFR-α.
Mouse knockout studies show that PDGF-C is required for palatogenesis. Although human studies support an etiologic role for several genes in cleft lip and palate etiology (PVRL1, IRF6, and MSX1), expression levels of the mouse homologs of these genes were unaltered in Pdgfc−/− mutant embryos that develop clefts, suggesting that their activity is not related to PDGF-C signaling in palatogenesis, so PDGF-C signaling is a new pathway in palatogenesis.
# Interactions
PDGFC has been shown to interact with PDGFRA.
PDGF-C is a latent growth factor with proteolytic activation, and the processing enzyme might be controlled by the other CLP-associated genes that may indirectly connect to PDGF-C signaling. Notably, a 30-cM region on human chromosome 4, where the PDGFC gene maps, shows strong linkage association with CLP26, and clinical genetic data further suggest a potential link between PDGFC gene polymorphism and cleft lip and palate. | PDGFC
Platelet-derived growth factor C, also known as PDGF-C, is a 345-amino acid protein that in humans is encoded by the PDGFC gene.[1][2] Platelet-derived growth factors are important in connective tissue growth, survival and function, and consist of disulphide-linked dimers involving two polypeptide chains, PDGF-A and PDGF-B. PDGF-C is a member of the PDGF/VEGF family of growth factors with a unique two-domain structure and expression pattern. PDGF-C was not previously identified with PDGF-A and PDGF-B, possibly because it may be that it is synthesized and secreted as a latent growth factor, requiring proteolytic removal of the N-terminal CUB domain for receptor binding and activation.[3]
# Function
The protein encoded by this gene is a member of the platelet-derived growth factor family. The four members of this family are mitogenic factors for cells of mesenchymal origin and are characterized by a core motif of eight cysteines. This gene product appears to form only homodimers. It differs from the platelet-derived growth factor alpha and beta polypeptides in having an unusual N-terminal domain, the CUB domain.[2]
PDGF-C is a key component of the PDGFR-α signaling pathway and has a specific role in palatogenesis and the morphogenesis of the integumentary tissue. The phenotypes of compound mutants imply that PDGF-C and PDGF-A may function as principal ligands for PDGFR-α.[4]
Mouse knockout studies show that PDGF-C is required for palatogenesis. Although human studies support an etiologic role for several genes in cleft lip and palate etiology (PVRL1, IRF6, and MSX1), expression levels of the mouse homologs of these genes were unaltered in Pdgfc−/− mutant embryos that develop clefts, suggesting that their activity is not related to PDGF-C signaling in palatogenesis, so PDGF-C signaling is a new pathway in palatogenesis.[5]
# Interactions
PDGFC has been shown to interact with PDGFRA.[6]
PDGF-C is a latent growth factor with proteolytic activation, and the processing enzyme might be controlled by the other CLP-associated genes that may indirectly connect to PDGF-C signaling. Notably, a 30-cM region on human chromosome 4, where the PDGFC gene maps, shows strong linkage association with CLP26, and clinical genetic data further suggest a potential link between PDGFC gene polymorphism and cleft lip and palate.[4] | https://www.wikidoc.org/index.php/PDGFC | |
46d63084e228037a79f707b175ea268504dee26c | wikidoc | PDS5B | PDS5B
Sister chromatid cohesion protein PDS5 homolog B is a protein that in humans is encoded by the PDS5B gene.
# Model organisms
Model organisms have been used in the study of PDS5B function. A conditional knockout mouse line, called Pds5btm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.
Twenty three tests were carried out and two phenotypes were reported. Almost all homozygous mutant animals died prior to birth, and therefore they did not survive until weaning. The remaining tests were carried out on heterozygous mutant mice, and no significant abnormalities were observed. | PDS5B
Sister chromatid cohesion protein PDS5 homolog B is a protein that in humans is encoded by the PDS5B gene.[1][2][3]
# Model organisms
Model organisms have been used in the study of PDS5B function. A conditional knockout mouse line, called Pds5btm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12]
Twenty three tests were carried out and two phenotypes were reported. Almost all homozygous mutant animals died prior to birth, and therefore they did not survive until weaning. The remaining tests were carried out on heterozygous mutant mice, and no significant abnormalities were observed.[5] | https://www.wikidoc.org/index.php/PDS5B | |
e1c9c6e1973eab421fed6d7387f23149fb6a4c37 | wikidoc | PEG10 | PEG10
Retrotransposon-derived protein PEG10 is a protein that in humans is encoded by the PEG10 gene.
# Function
This gene includes two overlapping reading frames of the same transcript encoding distinct isoforms. The shorter isoform has a CCHC-type zinc finger motif containing a sequence characteristic of gag proteins of most retroviruses and some retrotransposons, and it functions in part by interacting with members of the TGF-beta receptor family. The longer isoform has the active-site DSG consensus sequence of the protease domain of pol proteins. The longer isoform is the result of -1 translational frameshifting that is also seen in some retroviruses. Expression of these two isoforms only comes from the paternal allele due to imprinting. Increased gene expression (as observed by an increase in mRNA levels) is associated with hepatocellular carcinomas.
PEG10 is a paternally expressed imprinted gene that is expressed in adult and embryonic tissues. Most notable expression occurs in the placenta. This gene is highly conserved across mammalian species and retains the heptanucleotide (GGGAAAC). This gene has been reported to play a role in cell proliferation, differentiation and apoptosis. Overexpression of this gene has been associated with several malignancies, such as hepatocellular carcinoma and B-cell lymphocytic leukemia. Knockout mice lacking this gene showed early embryonic lethality with placental defects, indicating the importance of this gene in embryonic development. In preeclampsia placental tissue, PEG10 has been shown to be downregulated and upregulated implicating it as a possible causal role in the occurrence of preeclampsia.
# Interactions
PEG10 has been shown to interact with SIAH2 and SIAH1. | PEG10
Retrotransposon-derived protein PEG10 is a protein that in humans is encoded by the PEG10 gene.[1][2][3][4]
# Function
This gene includes two overlapping reading frames of the same transcript encoding distinct isoforms. The shorter isoform has a CCHC-type zinc finger motif containing a sequence characteristic of gag proteins of most retroviruses and some retrotransposons, and it functions in part by interacting with members of the TGF-beta receptor family. The longer isoform has the active-site DSG consensus sequence of the protease domain of pol proteins. The longer isoform is the result of -1 translational frameshifting that is also seen in some retroviruses. Expression of these two isoforms only comes from the paternal allele due to imprinting. Increased gene expression (as observed by an increase in mRNA levels) is associated with hepatocellular carcinomas.[4]
PEG10 is a paternally expressed imprinted gene that is expressed in adult and embryonic tissues.[5] Most notable expression occurs in the placenta. This gene is highly conserved across mammalian species and retains the heptanucleotide (GGGAAAC). This gene has been reported to play a role in cell proliferation, differentiation and apoptosis. Overexpression of this gene has been associated with several malignancies, such as hepatocellular carcinoma and B-cell lymphocytic leukemia. Knockout mice lacking this gene showed early embryonic lethality with placental defects, indicating the importance of this gene in embryonic development. In preeclampsia placental tissue, PEG10 has been shown to be downregulated[6] and upregulated[7] implicating it as a possible causal role in the occurrence of preeclampsia.
# Interactions
PEG10 has been shown to interact with SIAH2[8] and SIAH1.[8] | https://www.wikidoc.org/index.php/PEG10 | |
855ec1329a582a54fb34f194f589715d6e09c044 | wikidoc | PEPAP | PEPAP
PEPAP is an opioid analgesic that is an analogue of pethidine (meperidine).
It is related to the drug MPPP, with a phenethyl group in place of the 1-methyl substitution and an acetate ester rather than propionate.
PEPAP presumably has similar effects to other opioids, producing analgesia, sedation and euphoria. Side effects can include itching, nausea and potentially serious respiratory depression which can be life-threatening.
PEPAP could be particularly dangerous as it has been found to be a potent CYP2D6 inhibitor, which makes it likely to cause adverse interactions with some other drugs.
It is however not known whether the byproducts formed during the synthesis of PEPAP are neurotoxic in the same way as the MPPP byproduct MPTP. | PEPAP
PEPAP is an opioid analgesic that is an analogue of pethidine (meperidine).
It is related to the drug MPPP, with a phenethyl group in place of the 1-methyl substitution and an acetate ester rather than propionate.
PEPAP presumably has similar effects to other opioids, producing analgesia, sedation and euphoria. Side effects can include itching, nausea and potentially serious respiratory depression which can be life-threatening.
PEPAP could be particularly dangerous as it has been found to be a potent CYP2D6 inhibitor, which makes it likely to cause adverse interactions with some other drugs.[1]
It is however not known whether the byproducts formed during the synthesis of PEPAP are neurotoxic in the same way as the MPPP byproduct MPTP.
Template:Pharm-stub | https://www.wikidoc.org/index.php/PEPAP | |
9ae6ef74b319e72db7521292a54c0ddf2118bdfc | wikidoc | PEX10 | PEX10
Peroxisome biogenesis factor 10 is a protein that in humans is encoded by the PEX10 gene. Alternative splicing results in two transcript variants encoding different isoforms.
# Function
Peroxisome biogenesis factor 10 is involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane.
# Clinical significance
Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome.
# Interactions
PEX10 has been shown to interact with PEX12 and PEX19. | PEX10
Peroxisome biogenesis factor 10 is a protein that in humans is encoded by the PEX10 gene.[1][2] Alternative splicing results in two transcript variants encoding different isoforms.
# Function
Peroxisome biogenesis factor 10 is involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane.[2]
# Clinical significance
Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome.[2]
# Interactions
PEX10 has been shown to interact with PEX12[3][4] and PEX19.[5][6] | https://www.wikidoc.org/index.php/PEX10 | |
47bd66388b8a061a8c6f6e51401c181e7273cb79 | wikidoc | PEX12 | PEX12
Peroxisome assembly protein 12 is a protein that in humans is encoded by the PEX12 gene.
# Function
PEX12 is needed for protein import into peroxisomes. This gene belongs to the peroxin-12 family. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes.
# Clinical significance
The peroxisome biogenesis disorders (PBDs; MIM 601539) are a group of genetically heterogeneous diseases that are usually lethal in early infancy. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. This cellular phenotype is shared by yeast 'pex' mutants, and human orthologs of yeast PEX genes defective in some PBD complementation groups (CGs).
# Interactions
PEX12 has been shown to interact with PEX10, PEX5 and PEX19. | PEX12
Peroxisome assembly protein 12 is a protein that in humans is encoded by the PEX12 gene.[1][2]
# Function
PEX12 is needed for protein import into peroxisomes.[3] This gene belongs to the peroxin-12 family. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes.
# Clinical significance
The peroxisome biogenesis disorders (PBDs; MIM 601539) are a group of genetically heterogeneous diseases that are usually lethal in early infancy. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. This cellular phenotype is shared by yeast 'pex' mutants, and human orthologs of yeast PEX genes defective in some PBD complementation groups (CGs).[2]
# Interactions
PEX12 has been shown to interact with PEX10,[4][5] PEX5[4][5] and PEX19.[6][7] | https://www.wikidoc.org/index.php/PEX12 | |
f258afa6bef32e0841adc279cb675d97657c5536 | wikidoc | PGAM2 | PGAM2
Phosphoglycerate mutase 2 (PGAM2), also known as muscle-specific phosphoglycerate mutase (PGAM-M), is a phosphoglycerate mutase that, in humans, is encoded by the PGAM2 gene on chromosome 7.
Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a dimeric enzyme containing, in different tissues, different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase deficiency, also known as glycogen storage disease X.
# Structure
PGAM2 is one of two genes in humans encoding a PGAM subunit, the other being PGAM1.
## Gene
The PGAM2 gene is composed of three exons of lengths spanning 454, 180, and 202 bp, separated by two introns of 103 bp and 5.6 kb. Located 29 bp upstream of the transcription start site is a TATA box-like element, and 40 bp upstream of this element is an inverted CCAAT box element (ATTGG). Despite its muscle-specific expression, no muscle-specific consensus sequences were identified in the 5'-untranslated region of human PGAM2, though one consensus sequence has been proposed in rat and chicken. Unlike PGAM1, which is present as several copies in the human genome, only one copy of PGAM2 is found in the genome, indicating that this gene arose from gene duplication of and subsequent modifications in the PGAM1 gene.
## Protein
The isozyme encoded by PGAM2 spans 253 residues, which demonstrates highly sequence similarity (81% identity) to the protein PGAM1. Both form either homo- or heterodimers. The MM homodimer is found primarily in adult muscle, while the MB heterodimer, composed of a subunit from each isozyme, is found in the heart.
One key residue in the active site of PGAM2, lysine 100 (K100), is highly conserved across bacteria, to yeast, plant, and mammals, indicating its evolutionary importance. K100 directly contacts the substrate (3-PGA) and intermediate (2,3-PGA); however, the acetylation of this residue under normal cellular conditions neutralizes its positive charge and interferes with this binding.
# Mechanism
PGAM2 catalyzes the 3-PG-to-2-PG isomerization via a 2-step process:
- a phosphate group from the phosphohistidine in the active site is transferred to the C-2 carbon of 3-PGA to form 2,3-bisphosglycerate (2,3-PGA), and then
- the phosphate group linked to the C-3 carbon of 2,3-PG is transferred to the catalytic histidine to form 2-PGA and regenerate the phosphohistidine.
# Function
PGAM2 is one of two PGAM subunits found in humans and is predominantly expressed in adult muscle. Both isozymes of PGAM are glycolytic enzymes that catalyze the reversible conversion of 3-PGA to 2-PGA using 2,3-bisphosphoglycerate as a cofactor. Since both 3-PGA and 2-PGA are allosteric regulators of the pentose phosphate pathway (PPP) and glycine and serine synthesis pathways, respectively, PGAM2 may contribute to the biosynthesis of amino acids, 5-carbon sugar, and nucleotides precursors.
# Clinical significance
PGAM activity is upregulated in cancers, including lung cancer, colon cancer, liver cancer, breast cancer, and leukemia. One possible mechanism involves the deacetylation of residue K100 in the PGAM active site by sirtuin 2 (SIRT2) under conditions of oxidative stress. This deacetylation activates PGAM activity, resulting in increased NADPH production and cell proliferation, and thus tumor growth.
In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes. This PGAM2 deficiency results in a metabolic myopathy (glycogenosis type X) and has been traced to mutations in the PGAM2 gene. Currently, four mutations have been identified from African-American, Caucasian, and Japanese families. One G-to-A transition mutation in codon 78 produced a truncated protein product, while mutations at codons 89 and 90 may have disrupted the active site and resulted in an inactive protein product. Meanwhile, two patients heterozygous for the G97D mutation presented with exercise intolerance and muscle cramps.
# Interactions
PGAM2 is known to interact with:
- SIRT2.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | PGAM2
Phosphoglycerate mutase 2 (PGAM2), also known as muscle-specific phosphoglycerate mutase (PGAM-M), is a phosphoglycerate mutase that, in humans, is encoded by the PGAM2 gene on chromosome 7.[1][2]
Phosphoglycerate mutase (PGAM) catalyzes the reversible reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA) in the glycolytic pathway. The PGAM is a dimeric enzyme containing, in different tissues, different proportions of a slow-migrating muscle (MM) isozyme, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase deficiency, also known as glycogen storage disease X.[provided by RefSeq, Sep 2009][1]
# Structure
PGAM2 is one of two genes in humans encoding a PGAM subunit, the other being PGAM1.
## Gene
The PGAM2 gene is composed of three exons of lengths spanning 454, 180, and 202 bp, separated by two introns of 103 bp and 5.6 kb. Located 29 bp upstream of the transcription start site is a TATA box-like element, and 40 bp upstream of this element is an inverted CCAAT box element (ATTGG). Despite its muscle-specific expression, no muscle-specific consensus sequences were identified in the 5'-untranslated region of human PGAM2, though one consensus sequence has been proposed in rat and chicken.[3][4] Unlike PGAM1, which is present as several copies in the human genome, only one copy of PGAM2 is found in the genome, indicating that this gene arose from gene duplication of and subsequent modifications in the PGAM1 gene.[3]
## Protein
The isozyme encoded by PGAM2 spans 253 residues, which demonstrates highly sequence similarity (81% identity) to the protein PGAM1. Both form either homo- or heterodimers.[5] The MM homodimer is found primarily in adult muscle, while the MB heterodimer, composed of a subunit from each isozyme, is found in the heart.[4]
One key residue in the active site of PGAM2, lysine 100 (K100), is highly conserved across bacteria, to yeast, plant, and mammals, indicating its evolutionary importance. K100 directly contacts the substrate (3-PGA) and intermediate (2,3-PGA); however, the acetylation of this residue under normal cellular conditions neutralizes its positive charge and interferes with this binding.[5]
# Mechanism
PGAM2 catalyzes the 3-PG-to-2-PG isomerization via a 2-step process:
- a phosphate group from the phosphohistidine in the active site is transferred to the C-2 carbon of 3-PGA to form 2,3-bisphosglycerate (2,3-PGA), and then
- the phosphate group linked to the C-3 carbon of 2,3-PG is transferred to the catalytic histidine to form 2-PGA and regenerate the phosphohistidine.[5]
# Function
PGAM2 is one of two PGAM subunits found in humans and is predominantly expressed in adult muscle. Both isozymes of PGAM are glycolytic enzymes that catalyze the reversible conversion of 3-PGA to 2-PGA using 2,3-bisphosphoglycerate as a cofactor.[4][5][6] Since both 3-PGA and 2-PGA are allosteric regulators of the pentose phosphate pathway (PPP) and glycine and serine synthesis pathways, respectively, PGAM2 may contribute to the biosynthesis of amino acids, 5-carbon sugar, and nucleotides precursors.[5]
# Clinical significance
PGAM activity is upregulated in cancers, including lung cancer, colon cancer, liver cancer, breast cancer, and leukemia. One possible mechanism involves the deacetylation of residue K100 in the PGAM active site by sirtuin 2 (SIRT2) under conditions of oxidative stress. This deacetylation activates PGAM activity, resulting in increased NADPH production and cell proliferation, and thus tumor growth.[5]
In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes.[7] This PGAM2 deficiency results in a metabolic myopathy (glycogenosis type X) and has been traced to mutations in the PGAM2 gene. Currently, four mutations have been identified from African-American, Caucasian, and Japanese families.[8] One G-to-A transition mutation in codon 78 produced a truncated protein product, while mutations at codons 89 and 90 may have disrupted the active site and resulted in an inactive protein product.[6] Meanwhile, two patients heterozygous for the G97D mutation presented with exercise intolerance and muscle cramps.[8]
# Interactions
PGAM2 is known to interact with:
- SIRT2.[5]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/PGAM2 | |
5f843bb6fde0e5bb5640c6d675af200e554bae0b | wikidoc | PHKG2 | PHKG2
Phosphorylase b kinase gamma catalytic chain, testis/liver isoform is an enzyme that in humans is encoded by the PHKG2 gene.
The PHKG2 gene provides instructions for making one piece, the gamma subunit, of the phosphorylase b kinase enzyme. This enzyme is made up of 16 subunits, four each of the alpha, beta, gamma, and delta subunits. (Each subunit is produced from a different gene.) The gamma subunit performs the function of phosphorylase b kinase enzyme, and the other subunits help regulate its activity. This enzyme is found in various tissues, although it is most abundant in the liver and muscles. One version of the enzyme is found in liver cells and another in muscle cells. The gamma-2 subunit produced from the PHKG2 gene is part of the enzyme found in the liver.
Phosphorylase b kinase plays an important role in providing energy for cells. The main source of cellular energy is a simple sugar called glucose. Glucose is stored in muscle and liver cells in a form called glycogen. Glycogen can be broken down rapidly when glucose is needed, for instance to maintain normal levels of glucose in the blood between meals. Phosphorylase b kinase turns on (activates) another enzyme called glycogen phosphorylase b by converting it to the more active form, glycogen phosphorylase a. When active, this enzyme breaks down glycogen. | PHKG2
Phosphorylase b kinase gamma catalytic chain, testis/liver isoform is an enzyme that in humans is encoded by the PHKG2 gene.[1][2][3]
The PHKG2 gene provides instructions for making one piece, the gamma subunit, of the phosphorylase b kinase enzyme. This enzyme is made up of 16 subunits, four each of the alpha, beta, gamma, and delta subunits. (Each subunit is produced from a different gene.) The gamma subunit performs the function of phosphorylase b kinase enzyme, and the other subunits help regulate its activity. This enzyme is found in various tissues, although it is most abundant in the liver and muscles. One version of the enzyme is found in liver cells and another in muscle cells. The gamma-2 subunit produced from the PHKG2 gene is part of the enzyme found in the liver.[4]
Phosphorylase b kinase plays an important role in providing energy for cells. The main source of cellular energy is a simple sugar called glucose. Glucose is stored in muscle and liver cells in a form called glycogen. Glycogen can be broken down rapidly when glucose is needed, for instance to maintain normal levels of glucose in the blood between meals. Phosphorylase b kinase turns on (activates) another enzyme called glycogen phosphorylase b by converting it to the more active form, glycogen phosphorylase a. When active, this enzyme breaks down glycogen.[4] | https://www.wikidoc.org/index.php/PHKG2 | |
6a1f63864719009ea31ffbd717f549bdedf13bf4 | wikidoc | PHLPP | PHLPP
The PHLPP isoforms (PH domain and Leucine rich repeat Protein Phosphatases) are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases (Akt1, Akt2, Akt3) and conventional/novel protein kinase C (PKC) isoforms. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.
PHLPP dephosphorylates Ser-473 (the hydrophobic motif) in Akt, thus partially inactivating the kinase.
In addition, PHLPP dephosphorylates conventional and novel members of the protein kinase C family at their hydrophobic motifs, corresponding to Ser-660 in PKCβII.
# Domain structure
PHLPP is a member of the PPM family of phosphatases, which requires magnesium or manganese for their activity and are insensitive to most common phosphatase inhibitors, including . PHLPP1 and PHLPP2 have a similar domain structure, which includes a putative Ras association domain, a pleckstrin homology domain, a series of leucine-rich repeats, a PP2C phosphatase domain, and a C-terminal PDZ ligand. PHLPP1 has two splice variants, PHLPP1α and PHLPP1β, of which PHLPP1β is larger by approximately 1.5 kilobase pairs. PHLPP1α, which was the first PHLPP isoform to be characterized, lacks the N-terminal portion of the protein, including the Ras association domain. PHLPP's domain structure influences its ability to dephosphorylate its substrates. A PHLPP construct lacking the PH domain is unable to decrease PKC phosphorylation, while PHLPP lacking the PDZ ligand is unable to decrease Akt phosphorylation.
# Dephosphorylation of Akt
The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly dephosphorylate, and therefore inactivate, distinct Akt isoforms, at one of the two critical phosphorylation sites required for activation: Serine473. PHLPP2 dephosphorylates AKT1 and AKT3, whereas PHLPP1 is specific for AKT2 and AKT3. Lack of PHLPP appears to have effects on growth factor-induced Akt phosphorylation. When both PHLPP1 and PHLPP2 are knocked down using siRNA and cells are stimulated using epidermal growth factor, peak Akt phosphorylation at both Serine473 and Threonine308 (the other site required for full Akt activation) is increased dramatically.
## The Akt family of kinases
In humans, there are three genes in the Akt family: AKT1, AKT2, and AKT3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1).
Akt1 is involved in cellular survival pathways and inhibition of apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.
Akt2 is important in the insulin signaling pathway. It is required to induce glucose transport.
These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse that is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice that do not have Akt2 but have normal Akt1 have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway.
The role of Akt3 is less clear, though it appears to be expressed predominantly in brain. It has been reported that mice lacking Akt3 have small brains.
## Phosphorylation of Akt by PDK1 and PDK2
Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide-dependent kinase 1 (PDK1) and PDK2. Serine473, the hydrophobic motif, is phosphorylated in an mTORC2-dependent manner, leading some investigators to hypothesize that mTORC2 is the long-sought PDK2 molecule. Threonine308, the activation loop, is phosphorylated by PDK1, allowing full Akt activation. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. The PHLPPs therefore antagonize PDK1 and PDK2, since they dephosphorylate the site that PDK2 phosphorylates.
# Dephosphorylation of protein kinase C
PHLPP1 and 2 also dephosphorylate the hydrophobic motifs of two classes of the protein kinase C (PKC) family: the conventional PKCs and the novel PKCs. (The third class of PKCs, known as the atypicals, have a phospho-mimetic at the hydrophobic motif, rendering them insensitive to PHLPP.)
The PKC family of kinases consists of 10 isoforms, whose sensitivity to various second messengers is dictated by their domain structure. The conventional PKCs can be activated by calcium and diacylglycerol, two important mediators of G protein-coupled receptor signaling. The novel PKCs are activated by diacylglycerol but not calcium, while the atypical PKCs are activated by neither.
The PKC family, like Akt, plays roles in cell survival and motility. Most PKC isoforms are anti-apoptotic, although PKCδ (a novel PKC isoform) is pro-apoptotic in some systems.
Although PKC possesses the same phosphorylation sites as Akt, its regulation is quite different. PKC is constitutively phosphorylated, and its acute activity is regulated by binding of the enzyme to membranes. Dephosphorylation of PKC at the hydrophobic motif by PHLPP allows PKC to be dephosphorylated at two other sites (the activation loop and the turn motif). This in turn renders PKC sensitive to degradation. Thus, prolonged increases in PHLPP expression or activity inhibit PKC phosphorylation and stability, decreasing the total levels of PKC over time.
# Role in cancer
Investigators have hypothesized that the PHLPP isoforms may play roles in cancer, for several reasons. First, the genetic loci coding for PHLPP1 and 2 are commonly lost in cancer. The region including PHLPP1, 18q21.33, commonly undergoes loss of heterozygosity (LOH) in colon cancers, while 16q22.3, which includes the PHLPP2 gene, undergoes LOH in breast and ovarian cancers, Wilms tumors, prostate cancer and hepatocellular carcinoma. Second, experimental overexpression of PHLPP in cancer cell lines tends to decrease apoptosis and increase proliferation, and stable colon and glioblastoma cell lines overexpressing PHLPP1 show decreased tumor formation in xenograft models. Recent studies have also shown that Bcr-Abl, the fusion protein responsible for chronic myelogenous leukemia (CML), downregulates PHLPP1 and PHLPP2 levels, and that decreasing PHLPP levels interferes with the efficacy of Bcr-Abl inihibitors, including Gleevec, in CML cell lines.
Finally, both Akt and PKC are known to be tumor promoters, suggesting that their negative regulator PHLPP may act as a tumor suppressor. | PHLPP
The PHLPP isoforms (PH domain and Leucine rich repeat Protein Phosphatases) are a pair of protein phosphatases, PHLPP1 and PHLPP2, that are important regulators of Akt serine-threonine kinases (Akt1, Akt2, Akt3) and conventional/novel protein kinase C (PKC) isoforms. PHLPP may act as a tumor suppressor in several types of cancer due to its ability to block growth factor-induced signaling in cancer cells.[1]
PHLPP dephosphorylates Ser-473 (the hydrophobic motif) in Akt, thus partially inactivating the kinase.[2]
In addition, PHLPP dephosphorylates conventional and novel members of the protein kinase C family at their hydrophobic motifs, corresponding to Ser-660 in PKCβII.[3]
# Domain structure
PHLPP is a member of the PPM family of phosphatases, which requires magnesium or manganese for their activity and are insensitive to most common phosphatase inhibitors, including [okadaic acid]. PHLPP1 and PHLPP2 have a similar domain structure, which includes a putative Ras association domain, a pleckstrin homology domain, a series of leucine-rich repeats, a PP2C phosphatase domain, and a C-terminal PDZ ligand. PHLPP1 has two splice variants, PHLPP1α and PHLPP1β, of which PHLPP1β is larger by approximately 1.5 kilobase pairs. PHLPP1α, which was the first PHLPP isoform to be characterized, lacks the N-terminal portion of the protein, including the Ras association domain.[1] PHLPP's domain structure influences its ability to dephosphorylate its substrates. A PHLPP construct lacking the PH domain is unable to decrease PKC phosphorylation, while PHLPP lacking the PDZ ligand is unable to decrease Akt phosphorylation.[2]
# Dephosphorylation of Akt
The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly dephosphorylate, and therefore inactivate, distinct Akt isoforms, at one of the two critical phosphorylation sites required for activation: Serine473. PHLPP2 dephosphorylates AKT1 and AKT3, whereas PHLPP1 is specific for AKT2 and AKT3. Lack of PHLPP appears to have effects on growth factor-induced Akt phosphorylation. When both PHLPP1 and PHLPP2 are knocked down using siRNA and cells are stimulated using epidermal growth factor, peak Akt phosphorylation at both Serine473 and Threonine308 (the other site required for full Akt activation) is increased dramatically.[4]
## The Akt family of kinases
In humans, there are three genes in the Akt family: AKT1, AKT2, and AKT3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1).
Akt1 is involved in cellular survival pathways and inhibition of apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.
Akt2 is important in the insulin signaling pathway. It is required to induce glucose transport.
These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse that is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice that do not have Akt2 but have normal Akt1 have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway.[5]
The role of Akt3 is less clear, though it appears to be expressed predominantly in brain. It has been reported that mice lacking Akt3 have small brains.[6]
## Phosphorylation of Akt by PDK1 and PDK2
Once correctly positioned in the membrane via binding of PIP3, Akt can then be phosphorylated by its activating kinases, phosphoinositide-dependent kinase 1 (PDK1) and PDK2. Serine473, the hydrophobic motif, is phosphorylated in an mTORC2-dependent manner, leading some investigators to hypothesize that mTORC2 is the long-sought PDK2 molecule. Threonine308, the activation loop, is phosphorylated by PDK1, allowing full Akt activation. Activated Akt can then go on to activate or deactivate its myriad substrates via its kinase activity. The PHLPPs therefore antagonize PDK1 and PDK2, since they dephosphorylate the site that PDK2 phosphorylates.[1]
# Dephosphorylation of protein kinase C
PHLPP1 and 2 also dephosphorylate the hydrophobic motifs of two classes of the protein kinase C (PKC) family: the conventional PKCs and the novel PKCs. (The third class of PKCs, known as the atypicals, have a phospho-mimetic at the hydrophobic motif, rendering them insensitive to PHLPP.)
The PKC family of kinases consists of 10 isoforms, whose sensitivity to various second messengers is dictated by their domain structure. The conventional PKCs can be activated by calcium and diacylglycerol, two important mediators of G protein-coupled receptor signaling. The novel PKCs are activated by diacylglycerol but not calcium, while the atypical PKCs are activated by neither.
The PKC family, like Akt, plays roles in cell survival and motility. Most PKC isoforms are anti-apoptotic, although PKCδ (a novel PKC isoform) is pro-apoptotic in some systems.
Although PKC possesses the same phosphorylation sites as Akt, its regulation is quite different. PKC is constitutively phosphorylated, and its acute activity is regulated by binding of the enzyme to membranes. Dephosphorylation of PKC at the hydrophobic motif by PHLPP allows PKC to be dephosphorylated at two other sites (the activation loop and the turn motif). This in turn renders PKC sensitive to degradation. Thus, prolonged increases in PHLPP expression or activity inhibit PKC phosphorylation and stability, decreasing the total levels of PKC over time.[1]
# Role in cancer
Investigators have hypothesized that the PHLPP isoforms may play roles in cancer, for several reasons. First, the genetic loci coding for PHLPP1 and 2 are commonly lost in cancer. The region including PHLPP1, 18q21.33, commonly undergoes loss of heterozygosity (LOH) in colon cancers, while 16q22.3, which includes the PHLPP2 gene, undergoes LOH in breast and ovarian cancers, Wilms tumors, prostate cancer and hepatocellular carcinoma.[1] Second, experimental overexpression of PHLPP in cancer cell lines tends to decrease apoptosis and increase proliferation, and stable colon and glioblastoma cell lines overexpressing PHLPP1 show decreased tumor formation in xenograft models.[2][7] Recent studies have also shown that Bcr-Abl, the fusion protein responsible for chronic myelogenous leukemia (CML), downregulates PHLPP1 and PHLPP2 levels, and that decreasing PHLPP levels interferes with the efficacy of Bcr-Abl inihibitors, including Gleevec, in CML cell lines.[8]
Finally, both Akt and PKC are known to be tumor promoters, suggesting that their negative regulator PHLPP may act as a tumor suppressor. | https://www.wikidoc.org/index.php/PHLPP | |
3af41129951c7de976379258fe9db555e833d561 | wikidoc | PI4KA | PI4KA
Phosphatidylinositol 4-kinase alpha is an enzyme that in humans is encoded by the PI4KA gene.
# Function
This gene encodes a 1-phosphatidylinositol 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. Two transcript variants encoding different isoforms have been described for this gene.
# Clinical significance
The alpha isoform of PI4KIII plays a role in replication of hepatitis C virus (HCV). Furthermore, the PI4KA lipid kinase affects HCV replication by altering phosphorylation of the HCV NS5A protein. | PI4KA
Phosphatidylinositol 4-kinase alpha is an enzyme that in humans is encoded by the PI4KA gene.[1][2][3]
# Function
This gene encodes a 1-phosphatidylinositol 4-kinase which catalyzes the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. The mammalian PI 4-kinases have been classified into two types, II and III, based on their molecular mass, and modulation by detergent and adenosine. Two transcript variants encoding different isoforms have been described for this gene.[3]
# Clinical significance
The alpha isoform of PI4KIII plays a role in replication of hepatitis C virus (HCV).[4] Furthermore, the PI4KA lipid kinase affects HCV replication by altering phosphorylation of the HCV NS5A protein.[5] | https://www.wikidoc.org/index.php/PI4KA | |
8aba1d57605c546b9f4fffb0326293dbc1118682 | wikidoc | PI4KB | PI4KB
Phosphatidylinositol 4-kinase beta is an enzyme that in humans is encoded by the PI4KB gene.
# Classification
This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.
Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms
- phosphatidylinositol 4-kinase alpha (PI4KA)
- phosphatidylinositol 4-kinase beta (PI4KB)
- phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
- phosphatidylinositol 4-kinase 2-beta (PI4K2B)
# Function
Phosphatidylinositol 4-kinase beta (PI4KB) is a soluble protein shuttling between the cytoplasm and the nucleus, and can be recruited to the membranes of the Golgi system via protein-protein interactions, e.g. with small GTP binding proteins Arf1 and Rab11, or a Golgi adaptor protein ACBD3. PI4KB can be phosphorylated by the protein kinase D, which promotes the interaction with 14-3-3 proteins and stabilization of the protein in its active conformation. In cytoplasm PI4KB regulates the trafficking from the Golgi system to the plasma membrane, nevertheless, its nuclear function remains to be determined.
# Clinical significance
A wide range of positive-sense single-stranded RNA viruses (e.g. picornaviruses) including many important human pathogens hijack human PI4KB kinase to generate specific PI4P-enriched organelles called membranous webs. These organelles are then used as specific platforms for the effective viral replication within the host cell.
Furthermore, PI4KB homologue from the protozoan parasite Plasmodium falciparum has been identified as a target of imidopyrazines, an antimalarial compound class.
# Structure
PI4KB is composed of a proline-rich N-terminal region, a central helical domain, and a kinase domain located C-terminally. The N-terminal region contains a physiologically important binding site for a Golgi adaptor protein ACBD3, but is likely disordered and dispensable for the kinase activity. The central helical domain is responsible for the interaction with a small guanosine triphosphatase Rab11. The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in a cleft between the lobes. In addition, an ALPS motif has been identified in the extreme C-terminal region of PI4KB, which favors its association with unsaturated or loosely packed membranes regions. | PI4KB
Phosphatidylinositol 4-kinase beta is an enzyme that in humans is encoded by the PI4KB gene.[1][2][3]
# Classification
This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.
Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms
- phosphatidylinositol 4-kinase alpha (PI4KA)
- phosphatidylinositol 4-kinase beta (PI4KB)
- phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
- phosphatidylinositol 4-kinase 2-beta (PI4K2B)
# Function
Phosphatidylinositol 4-kinase beta (PI4KB) is a soluble protein shuttling between the cytoplasm and the nucleus,[4] and can be recruited to the membranes of the Golgi system via protein-protein interactions, e.g. with small GTP binding proteins Arf1[5] and Rab11,[6] or a Golgi adaptor protein ACBD3.[7][8] PI4KB can be phosphorylated by the protein kinase D,[9] which promotes the interaction with 14-3-3 proteins and stabilization of the protein in its active conformation.[10] In cytoplasm PI4KB regulates the trafficking from the Golgi system to the plasma membrane, nevertheless, its nuclear function remains to be determined.
# Clinical significance
A wide range of positive-sense single-stranded RNA viruses (e.g. picornaviruses) including many important human pathogens hijack human PI4KB kinase to generate specific PI4P-enriched organelles called membranous webs.[11] These organelles are then used as specific platforms for the effective viral replication within the host cell.
Furthermore, PI4KB homologue from the protozoan parasite Plasmodium falciparum has been identified as a target of imidopyrazines, an antimalarial compound class.[12]
# Structure
PI4KB is composed of a proline-rich N-terminal region, a central helical domain, and a kinase domain located C-terminally. The N-terminal region contains a physiologically important binding site for a Golgi adaptor protein ACBD3, but is likely disordered and dispensable for the kinase activity. The central helical domain is responsible for the interaction with a small guanosine triphosphatase Rab11. The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in a cleft between the lobes.[13] In addition, an ALPS motif has been identified in the extreme C-terminal region of PI4KB, which favors its association with unsaturated or loosely packed membranes regions.[14] | https://www.wikidoc.org/index.php/PI4KB | |
7066101a720febaa2635d8b25737adb96f2da0ee | wikidoc | PIAS3 | PIAS3
E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.
# PIAS family
The mammalian PIAS family consists of four members: PIAS1, PIAS2, PIAS3 and PIAS4. In Drosophila, a single PIAS homologue named dPIAS/Zimp has been identified. In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2. The PIAS family contains more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated through multiple mechanisms.
# Discovery
IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells. This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF, NFκB, SMAD and estrogen receptor.
# Function
PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.
# Domains
The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins. This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B. The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions. These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators. It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity. It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.
The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3. Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors. The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase. The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.
# Interactions
PIAS3 has been shown to interact with:
- GFI1,
- HMGA2
- MITF,
- SMAD2,
- SMAD3, and
- RELA.
# Related gene problems
- TAR syndrome
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | PIAS3
E3 SUMO-protein ligase PIAS3 is an enzyme that in humans is encoded by the PIAS3 gene.[1][2]
# PIAS family
The mammalian PIAS family consists of four members: PIAS1, PIAS2, PIAS3 and PIAS4. In Drosophila, a single PIAS homologue named dPIAS/Zimp has been identified.[3] In yeast, two PIAS-related proteins were identified namely SIZ1 and SIZ2.[4] The PIAS family contains more than 60 proteins, most of them transcription factors that can be either positively or negatively regulated through multiple mechanisms.
# Discovery
IAS proteins were originally identified in studies that were aimed to decipher the Janus Kinase (JAK)/STAT signaling pathway. Originally, PIAS3 was found to interact specifically with phosphorylated STAT3 in Interleukin -6 (IL-6) activated murine myeloblast M1 cells.[5] This interaction is mediated via PIAS3 binding to the STAT3 DNA binding domain. Hence, STAT3 transcriptional activity is inhibited by the physical prevention of its binding to target genes. Subsequently, PIAS3 was also found to be a regulator protein of other key transcription factors, including MITF,[6] NFκB,[7] SMAD[8] and estrogen receptor.[9]
# Function
PIAS3 protein also functions as a SUMO (small ubiquitin-like modifier)-E3 ligase which catalyzes the covalent attachment of a SUMO protein to specific target substrates. It directly binds to several transcription factors and either blocks or enhances their activity. Alternatively spliced transcript variants of this gene have been identified, but the full-length nature of some of these variants has not been determined.[2]
# Domains
The SAF-A/B, Acinus and PIAS (SAP) domain is located at the N-terminal of PIAS proteins.[10] This evolutionarily conserved domain is found in proteins ranging from yeast to human and is shared by other chromatin-binding proteins, such as scaffold attachment factor A and B.[11] The SAP domain can recognize and bind to AT-rich DNA sequences present in scaffold-attachment regions/matrix-attachment regions.[12] These elements are frequently found near gene enhancers and interact with nuclear matrix proteins to provide a unique nuclear microenvironment for transcriptional regulation. An LXXLL signature motif is present within the SAP domain of all PIAS proteins. This signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators.[13] It is also essential for the binding of PIAS3 to androgen receptor. The LXXLL motif represents the minimal requirement for the interaction with the NFκB p65 subunit and for the inhibition of NFκB transcriptional activity.[7] It was previously described that the LXXLL motif is also responsible for the retention of PIAS3 in the nucleus.
The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which was shown to be involved in the nuclear retention of PIAS3.[14] Within the PINIT domain, the PIAS382-132 region was isolated and characterized as an inhibitory domain that binds and inhibits both the MITF and STAT3 transcription factors.[15] The RING-finger-like zinc-binding domain (RLD) is one of the most conserved domains of the PIAS family and has been shown to be important for PIAS3 activity as a SUMO-E3 ligase.[16] The RLD domain is also involved in the positive regulation of SMAD3 by PIAS3.[17]
# Interactions
PIAS3 has been shown to interact with:
- GFI1,[18]
- HMGA2[19]
- MITF,[6][20]
- SMAD2,[21]
- SMAD3,[21] and
- RELA.[7]
# Related gene problems
- TAR syndrome[22]
- 1q21.1 deletion syndrome
- 1q21.1 duplication syndrome | https://www.wikidoc.org/index.php/PIAS3 | |
64af8096dd3552e14a37a83eb312be0dc6421d05 | wikidoc | PILRA | PILRA
Paired immunoglobin like type 2 receptor alpha is a protein that in humans is encoded by the PILRA gene.
# Function
Cell signaling pathways rely on a dynamic interaction between activating and inhibiting processes. SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways. Two types of inhibitory receptor superfamily members are immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors and their non-ITIM-bearing, activating counterparts.
Control of cell signaling via SHP-1 is thought to occur through a balance between PILRalpha-mediated inhibition and PILRbeta-mediated activation. These paired immunoglobulin-like receptor genes are located in a tandem head-to-tail orientation on chromosome 7. This particular gene encodes the ITIM-bearing member of the receptor pair, which functions in the inhibitory role. Alternative splicing has been observed at this locus, and three variants, each encoding a distinct isoform, are described. | PILRA
Paired immunoglobin like type 2 receptor alpha is a protein that in humans is encoded by the PILRA gene.
[1]
# Function
Cell signaling pathways rely on a dynamic interaction between activating and inhibiting processes. SHP-1-mediated dephosphorylation of protein tyrosine residues is central to the regulation of several cell signaling pathways. Two types of inhibitory receptor superfamily members are immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors and their non-ITIM-bearing, activating counterparts.
Control of cell signaling via SHP-1 is thought to occur through a balance between PILRalpha-mediated inhibition and PILRbeta-mediated activation. These paired immunoglobulin-like receptor genes are located in a tandem head-to-tail orientation on chromosome 7. This particular gene encodes the ITIM-bearing member of the receptor pair, which functions in the inhibitory role. Alternative splicing has been observed at this locus, and three variants, each encoding a distinct isoform, are described. | https://www.wikidoc.org/index.php/PILRA | |
1c97bdb900f238453965e6227b57e8f3dc1fa218 | wikidoc | PINK1 | PINK1
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.
It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to depolarized mitochondria to induce autophagy of those mitochondria. PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson's disease.
# Structure
PINK1 is synthesized as a 63000 Da protein which is often cleaved by PARL, between the 103-Alanine and the 104-Phenylalanine residues, into a 53000 Da fragment. PINK1 contains an N-terminal mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal regulatory sequence. The protein has been found to localize to the outer membrane of mitochondria, but can also be found throughout the cytosol. Experiments suggest the Ser/Thr kinase domain faces outward toward the cytosol, indicating a possible point of interaction with parkin.
The structure of PINK1 has been solved and shows how the protein binds and phosphorylates its substrate ubiquitin.
# Function
PINK1 is intimately involved with mitochondrial quality control by identifying damaged mitochondria and targeting specific mitochondria for degradation. Healthy mitochondria maintain a membrane potential that can be used to import PINK1 into the inner membrane where it is cleaved by PARL and cleared from the outer membrane. Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK1 then recruits parkin to target the damaged mitochondria for degradation through autophagy. Due to the presence of PINK1 throughout the cytoplasm, it has been suggested that PINK1 functions as a "scout" to probe for damaged mitochondria.
PINK1 may also control mitochondria quality through mitochondrial fission. Through mitochondrial fission, a number of daughter mitochondria are created, often with an uneven distribution in membrane potential. Mitochondria with a strong, healthy membrane potential were more likely to undergo fusion than mitochondria with a low membrane potential. Interference with the mitochondrial fission pathway led to an increase in oxidized proteins and a decrease in respiration. Without PINK1, parkin cannot efficiently localize to damaged mitochondria, while an over-expression of PINK1 causes parkin to localize to even healthy mitochondria. Furthermore, mutations in both Drp1, a mitochondrial fission factor, and PINK1 were fatal in Drosophila models. However, an over-expression of Drp1 could rescue subjects deficient in PINK1 or parkin, suggesting mitochondrial fission initiated by Drp1 recreates the same effects of the PINK1/parkin pathway.
In addition to mitochondrial fission, PINK1 has been implicated in mitochondrial motility. The accumulation of PINK1 and recruitment of parkin targets a mitochondria for degradation, and PINK1 may serve to enhance degradation rates by arresting mitochondrial motility. Over-expression of PINK1 produced similar effects to silencing Miro, a protein closely associated with mitochondrial migration.
Another mechanism of mitochondrial quality control may arise through mitochondria-derived vesicles. Oxidative stress in mitochondria can produce potentially harmful compounds including improperly folded proteins or reactive oxygen species. PINK1 has been shown to facilitate the creation of mitochondria-derived vesicles which can separate reactive oxygen species and shuttle them toward lysosomes for degradation.
# Disease relevance
Parkinson's disease is often characterized by the degeneration of dopaminergenic neurons and associated with the build-up of improperly folded proteins and Lewy bodies. Mutations in the PINK1 protein have been shown to lead to a build-up of such improperly folded proteins in the mitochondria of both fly and human cells. Specifically, mutations in the serine/threonine kinase domain have been found in a number of Parkinson's patients where PINK1 fails to protect against stress-induced mitochondrial dysfunction and apoptosis.
# Pharmacological manipulation
To date, there have been few reports of small molecules that activate PINK1 and their promise as potential treatments for Parkinson's disease. The first report appeared in 2013 when Kevan Shokat and his team from UCSF identified a nucleobase called kinetin as an activator of PINK1. Subsequently, it was shown by others that the nucleoside derivative of kinetin, i.e. kinetin riboside, exhibited significant activation of PINK1 in cells. Additionally, the monophosphate prodrugs of kinetin riboside, ProTides, also showed activation of PINK1. In December 2017, niclosamide, an anthelmintic drug, was identified as a potent activator of PINK1 in cells and in neurons. | PINK1
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.[1][2]
It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to depolarized mitochondria to induce autophagy of those mitochondria.[3][4] PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation.[5] Mutations in this gene cause one form of autosomal recessive early-onset Parkinson's disease.[6]
# Structure
PINK1 is synthesized as a 63000 Da protein which is often cleaved by PARL, between the 103-Alanine and the 104-Phenylalanine residues, into a 53000 Da fragment.[7] PINK1 contains an N-terminal mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal regulatory sequence. The protein has been found to localize to the outer membrane of mitochondria, but can also be found throughout the cytosol. Experiments suggest the Ser/Thr kinase domain faces outward toward the cytosol, indicating a possible point of interaction with parkin.[8]
The structure of PINK1 has been solved and shows how the protein binds and phosphorylates its substrate ubiquitin.[9]
# Function
PINK1 is intimately involved with mitochondrial quality control by identifying damaged mitochondria and targeting specific mitochondria for degradation. Healthy mitochondria maintain a membrane potential that can be used to import PINK1 into the inner membrane where it is cleaved by PARL and cleared from the outer membrane. Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK1 then recruits parkin to target the damaged mitochondria for degradation through autophagy.[10] Due to the presence of PINK1 throughout the cytoplasm, it has been suggested that PINK1 functions as a "scout" to probe for damaged mitochondria.[11]
PINK1 may also control mitochondria quality through mitochondrial fission. Through mitochondrial fission, a number of daughter mitochondria are created, often with an uneven distribution in membrane potential. Mitochondria with a strong, healthy membrane potential were more likely to undergo fusion than mitochondria with a low membrane potential. Interference with the mitochondrial fission pathway led to an increase in oxidized proteins and a decrease in respiration.[12] Without PINK1, parkin cannot efficiently localize to damaged mitochondria, while an over-expression of PINK1 causes parkin to localize to even healthy mitochondria.[13] Furthermore, mutations in both Drp1, a mitochondrial fission factor, and PINK1 were fatal in Drosophila models. However, an over-expression of Drp1 could rescue subjects deficient in PINK1 or parkin, suggesting mitochondrial fission initiated by Drp1 recreates the same effects of the PINK1/parkin pathway.[14]
In addition to mitochondrial fission, PINK1 has been implicated in mitochondrial motility. The accumulation of PINK1 and recruitment of parkin targets a mitochondria for degradation, and PINK1 may serve to enhance degradation rates by arresting mitochondrial motility. Over-expression of PINK1 produced similar effects to silencing Miro, a protein closely associated with mitochondrial migration.[15]
Another mechanism of mitochondrial quality control may arise through mitochondria-derived vesicles. Oxidative stress in mitochondria can produce potentially harmful compounds including improperly folded proteins or reactive oxygen species. PINK1 has been shown to facilitate the creation of mitochondria-derived vesicles which can separate reactive oxygen species and shuttle them toward lysosomes for degradation.[16]
# Disease relevance
Parkinson's disease is often characterized by the degeneration of dopaminergenic neurons and associated with the build-up of improperly folded proteins and Lewy bodies. Mutations in the PINK1 protein have been shown to lead to a build-up of such improperly folded proteins in the mitochondria of both fly and human cells.[17] Specifically, mutations in the serine/threonine kinase domain have been found in a number of Parkinson's patients where PINK1 fails to protect against stress-induced mitochondrial dysfunction and apoptosis.[18]
# Pharmacological manipulation
To date, there have been few reports of small molecules that activate PINK1 and their promise as potential treatments for Parkinson's disease. The first report appeared in 2013 when Kevan Shokat and his team from UCSF identified a nucleobase called kinetin as an activator of PINK1.[19] Subsequently, it was shown by others that the nucleoside derivative of kinetin, i.e. kinetin riboside, exhibited significant activation of PINK1 in cells.[20] Additionally, the monophosphate prodrugs of kinetin riboside, ProTides, also showed activation of PINK1.[21] In December 2017, niclosamide, an anthelmintic drug, was identified as a potent activator of PINK1 in cells and in neurons.[22] | https://www.wikidoc.org/index.php/PINK1 | |
db9ce884749de0631a920bc5cad1f9d1738df4b1 | wikidoc | PINX1 | PINX1
PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene. PINX1 is also known as PIN2 interacting protein 1. PINX1 is a telomerase inhibitor and a possible tumor suppressor.
# Interactions
PINX1 has been shown to interact with MCRS1, TERF1 and telomerase reverse transcriptase.
# Structure
There are two known variants of PINX1. The second variant “lacks an exon in the 3’ coding region which results in a frameshift compared to variant 1. The encoded isoform is shorter and has a distinct C-terminus compared to isoform 1.” There are three PINX1 cDNA clones. The longest one encodes a 328 amino acid 45kDa protein which contains an N-terminal Gly-rich patch and a C-terminal TID domain (telomerase inhibitory domain). The TRF1 binding domain is in the C-terminal 75 amino acids of PINX1. Mouse PINX1 is 74% identical to human PINX1. In other eukaryotes, including yeast, there is an overall 50% similarity to human PINX1.
# Function
Over-expression of PINX1 results in decreased telomerase activity, telomere shortening, and induction of crisis. Reduction of PINX1 leads to an increase in telomerase activity and elongation of telomeres. PINX1 differs from other proteins that regulate telomere length in that it acts on telomerase while other proteins adjust telomere length without affecting telomerase activity.
The PINX1 budding yeast orthologue Gnop1 inhibits telomerase by isolating the uncomplexed TERT protein so that it cannot associate with the telomerase template RNA, which prevents telomerase from being assembled. However, in humans, PINX1 impedes already assembled telomerase. PINX1 binds to N-terminus of hTERT and binds to hTR in the presence of hTERT. PINX1 binding to hTR “is correlated to the repressive function of PINX1 on telomerase, implying that the mode of telomerase enzyme inhibition by PINX1 may involve an associated with hTR....The effect of hPINX1 on telomerase appears to be exclusive of the G-patch region and is mediated instead by the C terminus of the protein. This suggests that hPINX1 may have functionally separable cellular effects in which the N terminus is involved in RNA processing via the G-patch, and the C terminus is involved in telomere dynamics.” It is suggested that “PINX1 represses telomerase activity in vivo by binding to the assembled hTERT-hTR complex.”
The TID domain of PINX1 is likely what binds to hTERT. In cells, full-length PINX1 is not as strong as just the TID domain at inhibiting telomerase. This may be due to full-length PINX1 being subject to “endogenous regulation such as posttranslational modifications to reduce its inhibitory activity.” Or it may be due to a reduction of the TID domain to bind and inhibit telomerase as a result of proteins interacting with PINX1, such as PIN2/TRF1 which colocalizes PINX1 in cells.
There are two types of PINX1: nuclear PINX1 which is associates with telomeres and CAC repeats and nucleolar PINX1 does not bind directly to the telomeres, but instead interacts with TRF1. Nucleolar hPINX1 mediates the movement of hTERT and TRF1 to the nucleolus. Over-expression of nucleolar hPINX1 leads to increased TRF1 in the nucleolus and binding to telomeres. However, this accumulation in the nucleolus was not found in ALT (alternative lengthening of telomeres) cells indicating that PINX1 function is telomerase dependent.
hPINX1 is found more in the nucleoplasm during the S phase which is also when telomerase is released into the nucleoplasm indicating that hPINX1 may inhibit telomerase during the S phase.
# Cancer
PINX1 is located at 8p23. Heterozygosity of this area is frequently lost in tumors including liver, prostate, prostate, colorectal, lung, and head and neck. Most PINX1 mutant tumors are carcinomas. PINX1 expression is significantly reduced in these tumors. This significance was shown with HT1080 cells, which increased tumorigenicity with decreased PINX1 expression. Over-expression of PINX1 in HT1080 cells did not allow them to form tumors in mice. Therefore, PINX1 may be a tumor suppressor.
PINX1 expression is a predictor of cervical squamous cell carcinoma (CSCC) cells response to cisplatin/paclitaxel chemotherapy. High levels of PINX1 correlated to response. But the levels of PINX1 were only associated with cytotoxicity of paclitaxel. Reduced levels of PINX1 led to increased paclitaxel cytotoxicity. “The ability of PINX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel.”
Chemoradiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). Reduced PINX1 expression did not affect ESCC cells response to 5-fluorouracil and cisplatin, but did increase efficacy of radiation therapy. High levels of PINX1 led to reduced cell death due to radiation. “PINX1 resistance to radiotherapy (RT) was attributed to PINX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe.” High levels of PINX1 is a predictor of short disease-specific survival.
PINX1 levels were found to be reduced in urothelial carcinoma of the bladder (UCB) compared to normal urothelial bladder epithelium. “PINX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index, and poor survival.” Over-expression of PINX1 reduced UCB cell proliferation and G1/S phase arrest. Knockdown PINX1 led to increased cell proliferation and accelerated G1/S transition.
PinX1 in other cancers:
- Ovarian
PINX1 in 100% of normal ovarian tissue and 66.2% of ovarian carcinomas
Decreased PINX1 expression related to poor prognostic factors and presence of lymph node metastasis
- PINX1 in 100% of normal ovarian tissue and 66.2% of ovarian carcinomas
- Decreased PINX1 expression related to poor prognostic factors and presence of lymph node metastasis
- Gastric
Loss of heterozygosity of PINX1 gene more common in lymph node metastasis and higher TNM stage
Microstatellite instability of PINX1 gene less frequent in cases with lymph node metastasis
Suppression of telomerase activity mediated by Mad1/c-Myc pathway
- Loss of heterozygosity of PINX1 gene more common in lymph node metastasis and higher TNM stage
- Microstatellite instability of PINX1 gene less frequent in cases with lymph node metastasis
- Suppression of telomerase activity mediated by Mad1/c-Myc pathway
- Esophageal
Over-expression of PINX1 inhibited cell growth, arrested cells at G0/G1, and induced apoptosis
- Over-expression of PINX1 inhibited cell growth, arrested cells at G0/G1, and induced apoptosis
- Nasopharyngeal
Over-expression of PINX1 decreased hTERT mRNA, reduced telomerase activity, inhibited cell growth, migration and would healing ability, arrested cells in G0/G1 phase, increased apoptosis
Down-regulation of PINX1 did not alter any of these characteristics
- Over-expression of PINX1 decreased hTERT mRNA, reduced telomerase activity, inhibited cell growth, migration and would healing ability, arrested cells in G0/G1 phase, increased apoptosis
- Down-regulation of PINX1 did not alter any of these characteristics
- Colorectal
Intact PINX1 and PINX1 without G-patch motif induce apoptosis, G1 arrest, and cellular senescence
Truncated PINX1 does not affect telomerase
- Intact PINX1 and PINX1 without G-patch motif induce apoptosis, G1 arrest, and cellular senescence
- Truncated PINX1 does not affect telomerase
- Cervical
Regulated by p53
- Regulated by p53 | PINX1
PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene.[1] PINX1 is also known as PIN2 interacting protein 1.[2] PINX1 is a telomerase inhibitor and a possible tumor suppressor.
# Interactions
PINX1 has been shown to interact with MCRS1,[3] TERF1[4] and telomerase reverse transcriptase.[4]
# Structure
There are two known variants of PINX1. The second variant “lacks an exon in the 3’ coding region which results in a frameshift compared to variant 1. The encoded isoform is shorter and has a distinct C-terminus compared to isoform 1.”[2] There are three PINX1 cDNA clones. The longest one encodes a 328 amino acid 45kDa protein which contains an N-terminal Gly-rich patch and a C-terminal TID domain (telomerase inhibitory domain). The TRF1 binding domain is in the C-terminal 75 amino acids of PINX1. Mouse PINX1 is 74% identical to human PINX1. In other eukaryotes, including yeast, there is an overall 50% similarity to human PINX1.[4][5]
# Function
Over-expression of PINX1 results in decreased telomerase activity, telomere shortening, and induction of crisis. Reduction of PINX1 leads to an increase in telomerase activity and elongation of telomeres. PINX1 differs from other proteins that regulate telomere length in that it acts on telomerase while other proteins adjust telomere length without affecting telomerase activity.[4]
The PINX1 budding yeast orthologue Gnop1 inhibits telomerase by isolating the uncomplexed TERT protein so that it cannot associate with the telomerase template RNA, which prevents telomerase from being assembled. However, in humans, PINX1 impedes already assembled telomerase. PINX1 binds to N-terminus of hTERT and binds to hTR in the presence of hTERT. PINX1 binding to hTR “is correlated to the repressive function of PINX1 on telomerase, implying that the mode of telomerase enzyme inhibition by PINX1 may involve an associated with hTR....The effect of hPINX1 on telomerase appears to be exclusive of the G-patch region and is mediated instead by the C terminus of the protein. This suggests that hPINX1 may have functionally separable cellular effects in which the N terminus is involved in RNA processing via the G-patch, and the C terminus is involved in telomere dynamics.”[6] It is suggested that “PINX1 represses telomerase activity in vivo by binding to the assembled hTERT-hTR complex.” [6]
The TID domain of PINX1 is likely what binds to hTERT. In cells, full-length PINX1 is not as strong as just the TID domain at inhibiting telomerase. This may be due to full-length PINX1 being subject to “endogenous regulation such as posttranslational modifications to reduce its inhibitory activity.”[4] Or it may be due to a reduction of the TID domain to bind and inhibit telomerase as a result of proteins interacting with PINX1, such as PIN2/TRF1 which colocalizes PINX1 in cells.[4]
There are two types of PINX1: nuclear PINX1 which is associates with telomeres and CAC repeats and nucleolar PINX1 does not bind directly to the telomeres, but instead interacts with TRF1. Nucleolar hPINX1 mediates the movement of hTERT and TRF1 to the nucleolus. Over-expression of nucleolar hPINX1 leads to increased TRF1 in the nucleolus and binding to telomeres. However, this accumulation in the nucleolus was not found in ALT (alternative lengthening of telomeres) cells indicating that PINX1 function is telomerase dependent.[7][8]
hPINX1 is found more in the nucleoplasm during the S phase which is also when telomerase is released into the nucleoplasm indicating that hPINX1 may inhibit telomerase during the S phase.[7]
# Cancer
PINX1 is located at 8p23. Heterozygosity of this area is frequently lost in tumors including liver, prostate, prostate, colorectal, lung, and head and neck. Most PINX1 mutant tumors are carcinomas. PINX1 expression is significantly reduced in these tumors. This significance was shown with HT1080 cells, which increased tumorigenicity with decreased PINX1 expression. Over-expression of PINX1 in HT1080 cells did not allow them to form tumors in mice. Therefore, PINX1 may be a tumor suppressor.[4][9]
PINX1 expression is a predictor of cervical squamous cell carcinoma (CSCC) cells response to cisplatin/paclitaxel chemotherapy. High levels of PINX1 correlated to response. But the levels of PINX1 were only associated with cytotoxicity of paclitaxel. Reduced levels of PINX1 led to increased paclitaxel cytotoxicity. “The ability of PINX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel.”[10]
Chemoradiotherapy is a standard treatment for advanced esophageal squamous cell carcinoma (ESCC). Reduced PINX1 expression did not affect ESCC cells response to 5-fluorouracil and cisplatin, but did increase efficacy of radiation therapy. High levels of PINX1 led to reduced cell death due to radiation. “PINX1 resistance to radiotherapy (RT) was attributed to PINX1 maintaining telomere stability, reducing ESCC cell death by RT-induced mitosis catastrophe.”[11] High levels of PINX1 is a predictor of short disease-specific survival.[11]
PINX1 levels were found to be reduced in urothelial carcinoma of the bladder (UCB) compared to normal urothelial bladder epithelium. “PINX1 levels were inversely correlated with tumor multiplicity, advanced N classification, high proliferation index, and poor survival.”[12] Over-expression of PINX1 reduced UCB cell proliferation and G1/S phase arrest. Knockdown PINX1 led to increased cell proliferation and accelerated G1/S transition.[12]
PinX1 in other cancers:
- Ovarian[13]
PINX1 in 100% of normal ovarian tissue and 66.2% of ovarian carcinomas
Decreased PINX1 expression related to poor prognostic factors and presence of lymph node metastasis
- PINX1 in 100% of normal ovarian tissue and 66.2% of ovarian carcinomas
- Decreased PINX1 expression related to poor prognostic factors and presence of lymph node metastasis
- Gastric[14][15][16]
Loss of heterozygosity of PINX1 gene more common in lymph node metastasis and higher TNM stage
Microstatellite instability of PINX1 gene less frequent in cases with lymph node metastasis
Suppression of telomerase activity mediated by Mad1/c-Myc pathway
- Loss of heterozygosity of PINX1 gene more common in lymph node metastasis and higher TNM stage
- Microstatellite instability of PINX1 gene less frequent in cases with lymph node metastasis
- Suppression of telomerase activity mediated by Mad1/c-Myc pathway
- Esophageal[17]
Over-expression of PINX1 inhibited cell growth, arrested cells at G0/G1, and induced apoptosis
- Over-expression of PINX1 inhibited cell growth, arrested cells at G0/G1, and induced apoptosis
- Nasopharyngeal[18]
Over-expression of PINX1 decreased hTERT mRNA, reduced telomerase activity, inhibited cell growth, migration and would healing ability, arrested cells in G0/G1 phase, increased apoptosis
Down-regulation of PINX1 did not alter any of these characteristics
- Over-expression of PINX1 decreased hTERT mRNA, reduced telomerase activity, inhibited cell growth, migration and would healing ability, arrested cells in G0/G1 phase, increased apoptosis
- Down-regulation of PINX1 did not alter any of these characteristics
- Colorectal[19]
Intact PINX1 and PINX1 without G-patch motif induce apoptosis, G1 arrest, and cellular senescence
Truncated PINX1 does not affect telomerase
- Intact PINX1 and PINX1 without G-patch motif induce apoptosis, G1 arrest, and cellular senescence
- Truncated PINX1 does not affect telomerase
- Cervical[20]
Regulated by p53
- Regulated by p53 | https://www.wikidoc.org/index.php/PINX1 | |
2274e9ad97646be82206f3b2341334836eb3b729 | wikidoc | PITX1 | PITX1
paired-like homeodomain 1 is a protein that in humans is encoded by the PITX1 gene.
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin.
# Clinical relevance
Mutations in this gene have been associated with autism, club foot and polydactyly in humans.
# Genetic Basis of Pathologies
Genomic rearrangements at the PITX1 locus are associated with Liebenberg syndrome. In PITX1 Liebenberg is associated with a translocation or deletions, which cause insert promoter groups into the PITX1 locus. A missense mutation within the PITX1 locus is associated with the development of autosomal dominant clubfoot.
# Interactions
PITX1 has been shown to interact with Pituitary-specific positive transcription factor 1. | PITX1
paired-like homeodomain 1 is a protein that in humans is encoded by the PITX1 gene.[1][2][3]
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family are involved in organ development and left-right asymmetry. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin.[3]
# Clinical relevance
Mutations in this gene have been associated with autism[4], club foot[5] and polydactyly[6] in humans.
# Genetic Basis of Pathologies
Genomic rearrangements at the PITX1 locus are associated with Liebenberg syndrome.[7] In PITX1 Liebenberg is associated with a translocation or deletions, which cause insert promoter groups into the PITX1 locus.[7] A missense mutation within the PITX1 locus is associated with the development of autosomal dominant clubfoot.[5]
# Interactions
PITX1 has been shown to interact with Pituitary-specific positive transcription factor 1.[8] | https://www.wikidoc.org/index.php/PITX1 | |
08e38b8c6e0ec642bdd86c0ddb86397f2f7bc505 | wikidoc | PITX2 | PITX2
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth and abdominal organs. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.
Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells. There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.
Studies have shown that in chick embryos , Pitx2 is a direct regulator of cVg1, a growth factor homologous to mammalian GDF1. cVg1 is a Transforming growth factor beta signal that is expressed posteriorly before the formation of the embryo germ layers. The Pitx2 regulation of cVg1 is essential both during normal embryonic development and during establishment of polarity in twins created by experimental division of a single, original embryo. Pitx2 is shown to be essential for upregulation of cVg1 through the binding of enhancers, and is necessary for the proper expression of cVg1 in the posterior marginal zone. Expression of cVg1 in the PMZ is in turn necessary for the proper development of the primitive streak. Experimental knockouts of the PITX2 gene are associated with the subsequent upregulation of related Pitx1, which is able to partially compensate for the loss of Pitx2. Pitx2's ability to regulate the polarity of the embryo may be responsible for the ability of developing chicks to establish proper polarity in embryos created by cuts performed as late as the blastoderm stage.
Pitx2 plays a role in limb myogenesis. Pitx2 can determine the development and activation of the MyoD gene (the gene responsible for skeletal myogenesis). Studies have shown that expression of Pitx2 happens before MyoD is expressed in muscles. Further studies show that Pitx2 is directly recruited to act on the MyoD core enhancer and thus, directing the expression of the MyoD gene. Pitx 2 is in a parallel pathway with Myf5 and Myf6, as both paths effect expression of MyoD. However, in the absence of the parallel pathway, Pitx2 can continue activating MyoD genes. The expression of Pitx2 saves MyoD gene expression and keeps expressing this gene for limb myogenesis. Yet, the Pitx 2 pathway is PAX3 dependent and requires this gene to enact limb myogenesis. Studies support this finding as in the absence of PAX3, there is Pitx2 expression deficit and thus, MyoD does not express itself in limb myogenesis. The Pitx2 gene is thus shown to be downstream of Pax3 and serve as an intermediate between Pax3 and MyoD. In conclusion, Pitx2 plays an integral role in limb myogenesis.
Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.
# Clinical significance
Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.
Pitx2 is overexpressed in many cancers. For example, thyroid, ovarian, and colon cancer all have higher levels of Pitx2 compared to noncancerous tissues. Scientists speculate that cancer cells improperly turn on Pitx2, leading to uncontrolled cell proliferation. This is consistent with the role of Pitx2 in regulating the growth-regulating genes cyclin D2, cyclin D1, and C-Myc.
In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1. Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1. Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents. In experiments where Pitx2 expression was decreased, renal cancer cells had decreased cell proliferation and greater susceptibility to doxorubicin treatment, which is consistent with other results.
In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells. In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC. Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression. Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.
In Congenital Heart Disease, heterozygous mutations in Pitx2 have been involved in the development of Tetralogy of Fallot, ventricular septal defects, atrial septal defects, transposition of great arteries, and endocardial cushion defect (ECD). The mutations of the Pitx2 gene are created through alternative splicing. The isoform of Pitx2 important for cardiogenesis is Pitx2c. The lack of expression of this particular isoform correlates with these congenital defects. Pitx2 mutations significantly reduce transcriptional activity of Pitx2 and synergistic activation between Pitx2 and NKX2(also important for development of the heart). The large phenotypic spectrum due to the mutation of Pitx2 may be attributed to a variety of factors including: different genetic backgrounds, epigenetic modifiers and delayed/complete penetrance. It is important to note that the mutation of Pitx2 is not defined as the cause of these congenital heart defects, but currently perceived as a risk factor for their development. | PITX2
Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.[1][2][3]
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor[4] and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth and abdominal organs. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.[3]
Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells.[5][6][7] There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.[8]
Studies have shown that in chick embryos , Pitx2 is a direct regulator of cVg1, a growth factor homologous to mammalian GDF1. cVg1 is a Transforming growth factor beta signal that is expressed posteriorly before the formation of the embryo germ layers.[9] The Pitx2 regulation of cVg1 is essential both during normal embryonic development and during establishment of polarity in twins created by experimental division of a single, original embryo. Pitx2 is shown to be essential for upregulation of cVg1 through the binding of enhancers, and is necessary for the proper expression of cVg1 in the posterior marginal zone. Expression of cVg1 in the PMZ is in turn necessary for the proper development of the primitive streak. Experimental knockouts of the PITX2 gene are associated with the subsequent upregulation of related Pitx1, which is able to partially compensate for the loss of Pitx2. Pitx2's ability to regulate the polarity of the embryo may be responsible for the ability of developing chicks to establish proper polarity in embryos created by cuts performed as late as the blastoderm stage.[10]
Pitx2 plays a role in limb myogenesis. Pitx2 can determine the development and activation of the MyoD gene (the gene responsible for skeletal myogenesis). Studies have shown that expression of Pitx2 happens before MyoD is expressed in muscles. Further studies show that Pitx2 is directly recruited to act on the MyoD core enhancer and thus, directing the expression of the MyoD gene. Pitx 2 is in a parallel pathway with Myf5 and Myf6, as both paths effect expression of MyoD. However, in the absence of the parallel pathway, Pitx2 can continue activating MyoD genes. The expression of Pitx2 saves MyoD gene expression and keeps expressing this gene for limb myogenesis. Yet, the Pitx 2 pathway is PAX3 dependent and requires this gene to enact limb myogenesis. Studies support this finding as in the absence of PAX3, there is Pitx2 expression deficit and thus, MyoD does not express itself in limb myogenesis. The Pitx2 gene is thus shown to be downstream of Pax3 and serve as an intermediate between Pax3 and MyoD. In conclusion, Pitx2 plays an integral role in limb myogenesis.[11]
Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.[12]
# Clinical significance
Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.[3]
Pitx2 is overexpressed in many cancers. For example, thyroid,[13] ovarian,[14] and colon cancer[15] all have higher levels of Pitx2 compared to noncancerous tissues. Scientists speculate that cancer cells improperly turn on Pitx2, leading to uncontrolled cell proliferation. This is consistent with the role of Pitx2 in regulating the growth-regulating genes cyclin D2,[16] cyclin D1,[17] and C-Myc.[17]
In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1.[18] Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1.[18] Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents.[18] In experiments where Pitx2 expression was decreased, renal cancer cells had decreased cell proliferation and greater susceptibility to doxorubicin treatment, which is consistent with other results.[18]
In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells.[19] In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC.[19] Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression.[19] Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.[19]
In Congenital Heart Disease, heterozygous mutations in Pitx2 have been involved in the development of Tetralogy of Fallot, ventricular septal defects, atrial septal defects, transposition of great arteries, and endocardial cushion defect (ECD).[20][21][22] The mutations of the Pitx2 gene are created through alternative splicing. The isoform of Pitx2 important for cardiogenesis is Pitx2c. The lack of expression of this particular isoform correlates with these congenital defects. Pitx2 mutations significantly reduce transcriptional activity of Pitx2 and synergistic activation between Pitx2 and NKX2(also important for development of the heart).[20] The large phenotypic spectrum due to the mutation of Pitx2 may be attributed to a variety of factors including: different genetic backgrounds, epigenetic modifiers and delayed/complete penetrance.[21] It is important to note that the mutation of Pitx2 is not defined as the cause of these congenital heart defects, but currently perceived as a risk factor for their development.[22] | https://www.wikidoc.org/index.php/PITX2 | |
aa8b10997142997ee985d450d6ed61428b3e31d5 | wikidoc | PITX3 | PITX3
Pituitary homeobox 3 is a protein that in humans is encoded by the PITX3 gene.
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development, and the specification and terminal differentiation of mesencephalic dopamine neurons in the substantia nigra compacta that are lost in Parkinson's disease.
# Clinical significance
Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts. | PITX3
Pituitary homeobox 3 is a protein that in humans is encoded by the PITX3 gene.[1][2]
# Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. Members of this family act as transcription factors. This protein is involved in lens formation during eye development,[2] and the specification and terminal differentiation of mesencephalic dopamine neurons in the substantia nigra compacta that are lost in Parkinson's disease.[3]
# Clinical significance
Mutations of this gene have been associated with anterior segment mesenchymal dysgenesis (ASMD) and congenital cataracts.[2] | https://www.wikidoc.org/index.php/PITX3 | |
013f1a7fda6321e397ed8979921b862be2372748 | wikidoc | PLCB1 | PLCB1
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-1 is an enzyme that in humans is encoded by the PLCB1 gene.
# Function
The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene.
# Interactions
PLCB1 has been shown to interact with TRPM7.
# Pathology
Homozygous PLCB1 deletion is associated with malignant migrating partial seizures in infancy. | PLCB1
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-1 is an enzyme that in humans is encoded by the PLCB1 gene.[1][2][3]
# Function
The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
PLCB1 has been shown to interact with TRPM7.[4]
# Pathology
Homozygous PLCB1 deletion is associated with malignant migrating partial seizures in infancy.[5] | https://www.wikidoc.org/index.php/PLCB1 | |
11b24f99273e9921a2422c1c36cd7e9aed1e1e46 | wikidoc | PLCB3 | PLCB3
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-3 is an enzyme that in humans is encoded by the PLCB3 gene.
The gene codes for the enzyme phospholipase C β3. The enzyme catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11, as well as G-beta gamma subunits.
# Interactions
PLCB3 has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2. | PLCB3
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase beta-3 is an enzyme that in humans is encoded by the PLCB3 gene.[1][2]
The gene codes for the enzyme phospholipase C β3. The enzyme catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11, as well as G-beta gamma subunits.
# Interactions
PLCB3 has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2.[3] | https://www.wikidoc.org/index.php/PLCB3 | |
db20a4853b42fabfe18d98eae7dbec2b91c67ad0 | wikidoc | PLCE1 | PLCE1
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) is an enzyme that in humans is encoded by the PLCE1 gene. This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Mutations in this gene cause early-onset nephrotic syndrome and have been associated with respiratory chain deficiency with diffuse mesangial sclerosis.
# Structure
PLCE1 is located on the q arm of chromosome 10 in position 23.33 and has 39 exons. PLCE1, the protein encoded by this gene, is located on the Golgi apparatus, the cell membrane, and in the cytosol. It contains 3 turns, 15 beta strands, and 6 alpha helixes. PLCE1 contains a 260 amino acid Ras-GEF domain at p. 531-790, a 149 amino acid PI-PLC X-box domain at p. 1392-1540, a 117 amino acid PI-PLC Y-box domain at p. 1730 – 1846, a 101 amino acid C2 domain at p. 1856 – 1956, a 103 amino acid Ras-associating 1 domain at p. 2012 – 2114, and a 104 amino acid Ras-associating 2 domain at p. 2135 – 2238. There is a region of 79 amino acids from p. 1686 – 1764 that is required for PLCE1 to be activated by RHOA, RHOB, GNA12, GNA13 and G-beta gamma. PLCE1 also has a Ca2+ cofactor. Alternative splicing results in multiple transcript variants encoding distinct isoforms.
# Function
PLCE1 belongs to the phospholipase family that catalyzes the hydrolysis of polyphosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Ins(1,4,5)P3 and diacylglycerol. These products initiate a cascade of intracellular responses that result in cell growth and differentiation and gene expression.
## Catalytic activity
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O = 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol.
# Clinical significance
Mutations in this gene cause early-onset nephrotic syndrome. This disease is characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis. Signs and symptoms include kidney biopsies demonstrating non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation as well as genetic tests revealing a pathogenic S1484L mutation. Diffuse mesangial proliferation is characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. This disease has also been associated with mitochondrial cytopathy stemming from respiratory chain deficiency primarily affecting complex IV.
Additionally, Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and it has been found that this protein is over expressed during heart failure. Research has suggested that PLCE1 may thus inhibit cardiac hypertrophy.
# Interactions
PLCE1 has been shown to have 12 binary protein-protein interactions including 8 co-complex interactions. PLCE1 appears to interact with RyR2, HRAS, NRAS, and LIMS1. | PLCE1
1-Phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLCE1) is an enzyme that in humans is encoded by the PLCE1 gene.[1][2] This gene encodes a phospholipase enzyme (PLCE1) that catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate to generate two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). Mutations in this gene cause early-onset nephrotic syndrome and have been associated with respiratory chain deficiency with diffuse mesangial sclerosis.[3][4]
# Structure
PLCE1 is located on the q arm of chromosome 10 in position 23.33 and has 39 exons.[3] PLCE1, the protein encoded by this gene, is located on the Golgi apparatus, the cell membrane, and in the cytosol. It contains 3 turns, 15 beta strands, and 6 alpha helixes. PLCE1 contains a 260 amino acid Ras-GEF domain at p. 531-790, a 149 amino acid PI-PLC X-box domain at p. 1392-1540, a 117 amino acid PI-PLC Y-box domain at p. 1730 – 1846, a 101 amino acid C2 domain at p. 1856 – 1956, a 103 amino acid Ras-associating 1 domain at p. 2012 – 2114, and a 104 amino acid Ras-associating 2 domain at p. 2135 – 2238. There is a region of 79 amino acids from p. 1686 – 1764 that is required for PLCE1 to be activated by RHOA, RHOB, GNA12, GNA13 and G-beta gamma. PLCE1 also has a Ca2+ cofactor.[2][5][6] Alternative splicing results in multiple transcript variants encoding distinct isoforms.[3]
# Function
PLCE1 belongs to the phospholipase family that catalyzes the hydrolysis of polyphosphoinositides such as phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate the second messengers Ins(1,4,5)P3 and diacylglycerol. These products initiate a cascade of intracellular responses that result in cell growth and differentiation and gene expression.[supplied by OMIM][3]
## Catalytic activity
1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + H2O = 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol.[1][2]
# Clinical significance
Mutations in this gene cause early-onset nephrotic syndrome. This disease is characterized by proteinuria, edema, and diffuse mesangial sclerosis or focal and segmental glomerulosclerosis.[3] Signs and symptoms include kidney biopsies demonstrating non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation as well as genetic tests revealing a pathogenic S1484L mutation. Diffuse mesangial proliferation is characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen.[7][5][6] This disease has also been associated with mitochondrial cytopathy stemming from respiratory chain deficiency primarily affecting complex IV.[4]
Additionally, Phospholipase C epsilon modulates beta-adrenergic receptor-dependent cardiac contraction and it has been found that this protein is over expressed during heart failure. Research has suggested that PLCE1 may thus inhibit cardiac hypertrophy.[8][5][6]
# Interactions
PLCE1 has been shown to have 12 binary protein-protein interactions including 8 co-complex interactions. PLCE1 appears to interact with RyR2, HRAS, NRAS, and LIMS1.[9] | https://www.wikidoc.org/index.php/PLCE1 | |
d8879b0359c0ffb8588bebc2ebecc1bbdeb0fbac | wikidoc | PLCG1 | PLCG1
Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.
# Function
The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RASGRP1 to translocate to the Golgi apparatus, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. The receptor protein tyrosine phosphatase PTPmu (PTPRM) is capable of dephosphorylating PLCG1. Two transcript variants encoding different isoforms have been found for this gene.
Common to all PLC isozymes, PLCG1 consists of an N-terminal PH domain, which translocates PLC to the plasma membrane and binds PIP3; four EF hands; an X and Y catalytic region comprising the TIM barrel; and a C-terminal C2 domain. Specific to the PLCG isozymes is a large separation between the X and Y domains consisting of a split PH domain, tandem SH2 domains, and an SH3 domain. The SH2 domains bind phosphorylated tyrosine residues on target proteins via their FLVR sequence motifs, activating the catalytic function of PLCg; and the SH3 domain binds to proline-rich sequences on the target protein.
PLCG1 can be activated by receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases. For example, when activated, fibroblast growth factor receptor 1 and epidermal growth factor receptor are RTKs that have phosphorylated tyrosines, which provide docking sites for PLCG1 SH2 domains. The activated RTKs phosphoylate PLCG1 at tyrosines located at position 472, 771, 775, 783, and 1254. Non-receptor tyrosine kinases interact with PLCG1 in large complexes at the plasma membrane. For example, in T cells, Lck and Fyn (Src family kinases) phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the T-cell antigen receptor (TCR). The phosphorylated ITAMs recruit ZAP-70, which phosphorylates tyrosines in LAT and SLP-76. PLCg1 binds to LAT through its n-terminal SH2 domain and to SLP-76 via its SH3 domain.
Has been shown to interact with CISH which negatively regulates it by targeting it for degradation. The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.
# Clinical significance
Researchers studying PLCg1 and its role in breast cancer metastasis discovered this gene can promote cancer metastasis and subsequently blocking it stopped cancer from spreading. Research is ongoing but this gene could lead to the development of new anti-cancer drugs.
# Interactions
PLCG1 has been shown to interact with:
- BAG3,
- CD117,
- CD31,
- Cbl gene
- CISH
- Epidermal growth factor receptor,
- Eukaryotic translation elongation factor 1 alpha 1,
- FLT1,
- GAB1,
- GIT1,
- Grb2,
- HER2/neu,
- IRS2,
- ITK,
- KHDRBS1,
- Linker of activated T cells,
- Lymphocyte cytosolic protein 2,
- PDGFRA,
- PLD2,
- RHOA,
- SOS1,
- TUB,
- TrkA,
- TrkB,
- VAV1, and
- Wiskott-Aldrich syndrome protein. | PLCG1
Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.[1][2]
# Function
The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RASGRP1 to translocate to the Golgi apparatus, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. The receptor protein tyrosine phosphatase PTPmu (PTPRM) is capable of dephosphorylating PLCG1.[3] Two transcript variants encoding different isoforms have been found for this gene.[4]
Common to all PLC isozymes, PLCG1 consists of an N-terminal PH domain, which translocates PLC to the plasma membrane and binds PIP3;[5] four EF hands; an X and Y catalytic region comprising the TIM barrel; and a C-terminal C2 domain.[6] Specific to the PLCG isozymes is a large separation between the X and Y domains consisting of a split PH domain, tandem SH2 domains, and an SH3 domain.[6] The SH2 domains bind phosphorylated tyrosine residues on target proteins via their FLVR sequence motifs, activating the catalytic function of PLCg; and the SH3 domain binds to proline-rich sequences on the target protein.[6]
PLCG1 can be activated by receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases. For example, when activated, fibroblast growth factor receptor 1 and epidermal growth factor receptor are RTKs that have phosphorylated tyrosines, which provide docking sites for PLCG1 SH2 domains.[6] The activated RTKs phosphoylate PLCG1 at tyrosines located at position 472, 771, 775, 783, and 1254.[7] Non-receptor tyrosine kinases interact with PLCG1 in large complexes at the plasma membrane. For example, in T cells, Lck and Fyn (Src family kinases) phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the T-cell antigen receptor (TCR).[6] The phosphorylated ITAMs recruit ZAP-70, which phosphorylates tyrosines in LAT and SLP-76. PLCg1 binds to LAT through its n-terminal SH2 domain and to SLP-76 via its SH3 domain.[6]
Has been shown to interact with CISH which negatively regulates it by targeting it for degradation.[8] The deletion of Cish in effector T cells has been shown to augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. There are no changes in activity or phosphorylation of Cish's purported target, STAT5 in either the presence or absence of Cish.
# Clinical significance
Researchers studying PLCg1 and its role in breast cancer metastasis discovered this gene can promote cancer metastasis and subsequently blocking it stopped cancer from spreading. Research is ongoing but this gene could lead to the development of new anti-cancer drugs.[9][10]
# Interactions
PLCG1 has been shown to interact with:
- BAG3,[11]
- CD117,[12][13]
- CD31,[14]
- Cbl gene[15][16]
- CISH[8]
- Epidermal growth factor receptor,[15][17]
- Eukaryotic translation elongation factor 1 alpha 1,[18]
- FLT1,[19]
- GAB1,[20][21]
- GIT1,[22]
- Grb2,[23][24][25]
- HER2/neu,[26][27]
- IRS2,[28]
- ITK,[29][30]
- KHDRBS1,[31][32][33]
- Linker of activated T cells,[34][35][36]
- Lymphocyte cytosolic protein 2,[37]
- PDGFRA,[38]
- PLD2,[39]
- RHOA,[40]
- SOS1,[25][41]
- TUB,[42]
- TrkA,[43][44][45][46]
- TrkB,[45][47]
- VAV1,[48] and
- Wiskott-Aldrich syndrome protein.[49][50] | https://www.wikidoc.org/index.php/PLCG1 | |
9023df83473aface8e9e78f772573bdd914819c1 | wikidoc | PMPCA | PMPCA
Mitochondrial-processing peptidase subunit alpha is an enzyme that in humans is encoded by the PMPCA gene. This gene PMPCA encoded a protein that is a member of the peptidase M16 family. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.
# Structure
The Mitochondrial-processing peptidase subunit alpha precursor protein is 58.2 KDa in size and composed of 525 amino acids. The precursor protein contains a 33 amino acid N-terminal fragment as mitochondrion targeting sequence. After cleavage, the matured PMPCA protein is 54.6 KDa in size and has a theoretical pI of 5.88.
# Function
Mitochondrial-processing peptidase (MPP) is a metalloendopeptidase, containing two structurally related subunits, Subunit alpha and mitochondrial-processing peptidase subunit beta, working in conjunction for its catalytic function. Containing the catalytic site, the beta subunit PMPCB protein cleaves presequences (transit peptides) from mitochondrial protein precursors and releases of N-terminal transit peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2.
# Interactions
As the alpha subunit of Mitochondrial-processing peptidase, PMPCA forms a heterodimer with the subunit PMPCB.
# Clinical significance
The majority of mitochondrial proteins is nuclear-coded, which necessitates proper translocations of mitochondrial targeting proteins. Many mitochondrial proteins are synthesized in a precursor form that contains mitochondria targeting sequence. These precursors are usually cleaved by peptidases and proteases before they arrive their sub-organellar locations. It is likely that altered activity of the mitochondrial processing peptidases is essential to ensure the correct maturation of mitochondrial proteins and that altered activity of these proteases will have dramatic effects in the activity, stability and assembly of mitochondrial proteins. Evidences showed that MPP was involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis. Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder | PMPCA
Mitochondrial-processing peptidase subunit alpha is an enzyme that in humans is encoded by the PMPCA gene.[1][2][3] This gene PMPCA encoded a protein that is a member of the peptidase M16 family. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.
# Structure
The Mitochondrial-processing peptidase subunit alpha precursor protein is 58.2 KDa in size and composed of 525 amino acids. The precursor protein contains a 33 amino acid N-terminal fragment as mitochondrion targeting sequence. After cleavage, the matured PMPCA protein is 54.6 KDa in size and has a theoretical pI of 5.88.
# Function
Mitochondrial-processing peptidase (MPP) is a metalloendopeptidase, containing two structurally related subunits, Subunit alpha and mitochondrial-processing peptidase subunit beta, working in conjunction for its catalytic function.[4] Containing the catalytic site, the beta subunit PMPCB protein cleaves presequences (transit peptides) from mitochondrial protein precursors and releases of N-terminal transit peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2.
# Interactions
As the alpha subunit of Mitochondrial-processing peptidase, PMPCA forms a heterodimer with the subunit PMPCB.
# Clinical significance
The majority of mitochondrial proteins is nuclear-coded, which necessitates proper translocations of mitochondrial targeting proteins. Many mitochondrial proteins are synthesized in a precursor form that contains mitochondria targeting sequence. These precursors are usually cleaved by peptidases and proteases before they arrive their sub-organellar locations. It is likely that altered activity of the mitochondrial processing peptidases is essential to ensure the correct maturation of mitochondrial proteins and that altered activity of these proteases will have dramatic effects in the activity, stability and assembly of mitochondrial proteins. Evidences showed that MPP was involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis.[5] Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder[6][7] | https://www.wikidoc.org/index.php/PMPCA | |
cb354a945f45badddba4fe2c5546692ce2feaadd | wikidoc | PMPCB | PMPCB
Mitochondrial-processing peptidase subunit beta is an enzyme that in humans is encoded by the PMPCB gene. This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.
# Structure
The Mitochondrial-processing peptidase subunit beta precursor protein is 54.4 KDa in size and composed of 489 amino acids. The precursor protein contains a 45 amino acid N-terminal fragment as mitochondrion targeting sequence. After cleavage, the matured PMPCB protein is 49.5 KDa in size and has a theoretical pI of 5.76.
# Function
Mitochondrial-processing peptidase (MPP) is a metalloendopeptidase, containing two structurally related subunits, mitochondrial-processing peptidase subunit alpha and subunit beta, working in conjunction for its catalytic function. Containing the catalytic site, the beta subunit PMPCB protein cleaves presequences (transit peptides) from mitochondrial protein precursors and releases of N-terminal transit peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2.
# Interactions
As the beta subunit of Mitochondrial-processing peptidase, PMPCB forms a heterodimer with the subunit Mitochondrial-processing peptidase subunit alpha. In addition, PMPCB has been shown to interact with PMPCA and Frataxin.
# Clinical significance
The majority of mitochondrial proteins is nuclear-coded, which necessitates proper translocations of mitochondrial targeting proteins. Many mitochondrial proteins are synthesized in a precursor form that contains mitochondria targeting sequence. These precursors are usually cleaved by peptidases and proteases before they arrive their sub-organellar locations. It is likely that altered activity of the mitochondrial processing peptidases is essential to ensure the correct maturation of mitochondrial proteins and that altered activity of these proteases will have dramatic effects in the activity, stability and assembly of mitochondrial proteins. Evidences showed that MPP was involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis. Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder | PMPCB
Mitochondrial-processing peptidase subunit beta is an enzyme that in humans is encoded by the PMPCB gene.[1][2] This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.[2]
# Structure
The Mitochondrial-processing peptidase subunit beta precursor protein is 54.4 KDa in size and composed of 489 amino acids. The precursor protein contains a 45 amino acid N-terminal fragment as mitochondrion targeting sequence. After cleavage, the matured PMPCB protein is 49.5 KDa in size and has a theoretical pI of 5.76.
# Function
Mitochondrial-processing peptidase (MPP) is a metalloendopeptidase, containing two structurally related subunits, mitochondrial-processing peptidase subunit alpha and subunit beta, working in conjunction for its catalytic function.[3] Containing the catalytic site, the beta subunit PMPCB protein cleaves presequences (transit peptides) from mitochondrial protein precursors and releases of N-terminal transit peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2.
# Interactions
As the beta subunit of Mitochondrial-processing peptidase, PMPCB forms a heterodimer with the subunit Mitochondrial-processing peptidase subunit alpha. In addition, PMPCB has been shown to interact with PMPCA and Frataxin.[4]
# Clinical significance
The majority of mitochondrial proteins is nuclear-coded, which necessitates proper translocations of mitochondrial targeting proteins. Many mitochondrial proteins are synthesized in a precursor form that contains mitochondria targeting sequence. These precursors are usually cleaved by peptidases and proteases before they arrive their sub-organellar locations. It is likely that altered activity of the mitochondrial processing peptidases is essential to ensure the correct maturation of mitochondrial proteins and that altered activity of these proteases will have dramatic effects in the activity, stability and assembly of mitochondrial proteins. Evidences showed that MPP was involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis.[5] Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder[6][7] | https://www.wikidoc.org/index.php/PMPCB | |
50b004cd0cafddf77183afe990e391bbdf44c817 | wikidoc | PODXL | PODXL
Podocalyxin-like protein 1 is a protein that in humans is encoded by the PODXL gene.
# Function
This gene encodes a member of the CD34 sialomucin protein family. The encoded protein was originally identified as an important component of glomerular podocytes. Inactivation of the encoding gene in mice leads to anuria, omphalocele and perinatal death. Podocytes are highly differentiated epithelial cells with interdigitating foot processes covering the outer aspect of the glomerular basement membrane. Other biological activities of the encoded protein include: binding in a membrane protein complex with Na+/H+ exchanger regulatory factor to intracellular cytoskeletal elements, playing a role in hematopoetic cell differentiation, and being expressed in vascular endothelium cells and binding to L-selectin.
# Expression
The expression and localisation of PODXL in human cells, tissues and organs have been investigated by the Human Protein Atlas consortium. According to antibody-based profiling, the protein is present in glomerular podocytes, endothelial cells, glandular cells in fallopian tube, uterus and seminal vesicle and according to RNA expression analysis, the PODXL transcripts are present in all analysed human tissues. Based on confocal microscopy, the protein is mainly localised to the plasma membrane and microtubule organizing center and in addition localized to vesicles.
# Interactions
PODXL has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2.
# Clinical significance
Podocalyxin is upregulated in a number of cancers and is frequently associated with poor prognosis. Based on patient survival data, high level of PODXL transcripts in tumor cells is associated with poor prognosis in renal cancer. | PODXL
Podocalyxin-like protein 1 is a protein that in humans is encoded by the PODXL gene.[1]
# Function
This gene encodes a member of the CD34 sialomucin protein family.[2] The encoded protein was originally identified as an important component of glomerular podocytes. Inactivation of the encoding gene in mice leads to anuria, omphalocele and perinatal death.[3] Podocytes are highly differentiated epithelial cells with interdigitating foot processes covering the outer aspect of the glomerular basement membrane. Other biological activities of the encoded protein include: binding in a membrane protein complex with Na+/H+ exchanger regulatory factor to intracellular cytoskeletal elements, playing a role in hematopoetic cell differentiation, and being expressed in vascular endothelium cells and binding to L-selectin.[1]
# Expression
The expression and localisation of PODXL in human cells, tissues and organs have been investigated by the Human Protein Atlas consortium[4]. According to antibody-based profiling, the protein is present in glomerular podocytes, endothelial cells, glandular cells in fallopian tube, uterus and seminal vesicle and according to RNA expression analysis, the PODXL transcripts are present in all analysed human tissues[5]. Based on confocal microscopy[6], the protein is mainly localised to the plasma membrane and microtubule organizing center and in addition localized to vesicles[7].
# Interactions
PODXL has been shown to interact with Sodium-hydrogen exchange regulatory cofactor 2.[8][9][10]
# Clinical significance
Podocalyxin is upregulated in a number of cancers and is frequently associated with poor prognosis[11][12]. Based on patient survival data[13], high level of PODXL transcripts in tumor cells is associated with poor prognosis in renal cancer. | https://www.wikidoc.org/index.php/PODXL | |
a6933fb846b4204b6bbc0b67f559e8a90859b91a | wikidoc | POLD1 | POLD1
The gene polymerase delta 1 (POLD1) encodes the large, POLD1/p125, catalytic subunit of the DNA polymerase delta (Polδ) complex. The Polδ enzyme is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand (Figure 1). The POLD1/p125 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage. Germline mutations impairing activity of POLD1 have been implicated in several types of hereditary cancer, in some sporadic cancers, and in a developmental syndrome of premature aging, Mandibular hypoplasia, Deafness, and Progeroid features and Lipodystrophy (MDPL/MDP syndrome). Studies of POLD1 emphasize the importance of maintaining genomic stability to limit tumorigenesis. It is currently unclear whether the enhanced tumorigenesis associated with POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks (DSBs). Recent reviews have addressed important functions of POLD1 and Polδ.
# Discovery
The first DNA polymerase, DNA polymerase I, was discovered by Arthur Kornberg and his colleagues in 1956, reviewed in. In 1976, Byrnes et al. discovered a third DNA polymerase activity in mammalian cells that was called polymerase delta (δ). It was purified from rabbit erythroid hyperplastic bone marrow and described as a DNA polymerase that possessed an intrinsic 3’ to 5’ exonuclease activity. A 3’-5’ exonuclease proofreading function for DNA polymerases (E. coli) had first been described 4 years earlier by Kornberg and Brutlag, reviewed in. The human DNA Polδ is a heterotetramer. The four subunits are: (POLD1/ p125), (POLD3/ p66), (POLD2/ p50) and (POLD4/ p12), with the alternative names reflecting the molecular weights expressed in kilodaltons (kDa). The polymerase catalytic subunit was identified as the 125 kDa polypeptide by activity staining in 1991. Several groups independently cloned the human and murine POLD1 cDNAs. Following its purification from various sources including calf thymus, human placenta, and HeLa cells, its activity was implicated in DNA repair.
# Gene
Polymerase (DNA) delta 1, catalytic subunit and POLD1 are the name and gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC). POLD1 is also known as CDC2, MDPL, POLD, and CRCS10), is ~34 kb long and its cytogenetic location is chromosome 19 q13.33. The precise location, in the GRCh38.p2 assembly, is from base pair 50,384,290 to base pair 50,418,018 on chromosome 19. The mouse orthologue maps to mouse chromosome 7. In humans, the major POLD1 transcript (NM_002691.3) contains 27 exons and translates into the 1107 amino acids of the p125 or A subunit. A longer isoform has been reported with a 26 amino acid in-frame insertion after amino acid 592 (NP_001295561.1). A pseudogene (LOC100422453) has been reported on the long arm of chromosome 6. Table 1 provides gene names and chromosomal locations for the various subunits of Polδ in humans, mice, budding yeast (S. cerevisiae) and fission yeast (S. pombe).
The POLD1 gene promoter is regulated via the cell cycle machinery and mRNA expression of POLD1 reaches a peak in late G1/S phase during DNA replication. The POLD1 promoter is G/C-rich and has no TATA box. The transcription of this GC box-containing promoter is regulated by Sp1 and Sp1-related transcription factors such as Sp3, with their binding mediated via 11-bp repeat binding sequences. The POLD1 promoter contains an E2F-like sequence located near the major transcription start site. Another regulatory element, the cell cycle element/cell cycle genes homology region (CDE/CHR), located downstream of the start site is important for POLD1 transcription in G2/M phase by E2F1 and p21 proteins. P53 regulates POLD1 transcription by indirect p21-dependent activation of a p53-p21-DREAM-CDE/CHR pathway. One study has reported that the p53 tumor suppressor protein competes with Sp1 for binding to the POLD1 promoter. A microRNA (miR), miR-155, downregulates POLD1 indirectly by suppressing the transcription factor FOXO3a, which has putative binding sites in the POLD1 promoter (RTMAAYA; response element).
# Protein
POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε). Human POLD1/p125 has a putative nuclear localization signal at the N-terminal end (residues 4-19). Residues 304-533 contain the exonuclease domain (Figure 2) while residues 579-974 contain the polymerase domain. The exonuclease domain is a DEDDy-type DnaQ-like domain common to the B-DNA polymerase family. This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.
Motifs A and C, which are the most conserved of the polymerase domain. These have 2 catalytic aspartates, in motif A (DXXLYPS, D602) and motif C (DTDS, D757) that bind calcium at the active site. Motif A has 11 amino acids that are important in nucleotide incorporation and formation of the phosphodiester bond.
Tyrosine Y701 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation. An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase of cell cycle. The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function. POLD1 can be targeted to the nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region. The C-terminal domain has two conserved cysteine-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for Proliferating Cell Nuclear Antigen (PCNA) binding and recruitment of accessory subunits respectively. CysB coordinates an cluster added through Cytosolic Iron-sulfur protein Assembly (CIA), which requires the function of the mitochondrial Iron Sulfur Cluster (ISC) assembly machinery. The maturation process is mediated by the core targeting complex CIA1-CIA2B/FAM96B-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.
Binding and association studies have shown that POLD2 is tightly associated with POLD1; POLD3 and POLD2 interact with each other and POLD4 interacts with both POLD1 and POLD2. Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from the calf thymus, and the complete holoenzyme was very strongly stimulated by PCNA. Numerous studies have shown that while POLD1 possesses both the polymerase and the 3’-5’ exonuclease proofreading activity, the other subunits increase these activities, DNA binding abilities, and functionally important interactions with PCNA and its clamp loader Replication Factor C (RFC). The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex (Figure 1).
A number of other studies and screens have identified additional interaction partners relevant to functions in DNA replication and repair. Figure 3 shows a matrix of established and putative interactions during replication and repair which can be further accessed through and. A website at Vanderbilt University provides additional interaction on important POLD1 protein structure and various classes of gene and protein interaction, based on criteria such as co-occurrence in a complex, direct physical interaction, regulatory relationship, and co-expression.
## Expression and regulation
The POLD1/P125 protein is expressed ubiquitously across a panel of human tissues with high levels in the heart and lung tissues. The subcellular localization of POLD1/p125 is predominantly in the nucleus and nucleoplasm.
A reduction in POLD1/p125 has been observed in senescent human skin fibroblasts and in lymphocytes from an elderly population. POLD1/p125 expression is epigenetically regulated in response to DNA damage. Other studies have also shown that POLD1/p125 expression is regulated by miR-155, p53 and by the long non-coding RNA, PVT1. In the presence of DNA damage or replication stress (UV light, methyl methanesulfonate, hydroxyurea or aphidicolin), the POLD4/p12 subunit is rapidly degraded. The catalytic activities of p125 are different whether it is in the heterotetramer (Polδ4, with p12 ) or in the heterotrimer (Polδ3, without p12). The production of the heterotrimer depends on p12 degradation by the E3 ligase RNF8, a protein involved in DSBs repair and possibly homologous recombination (HR). In addition, the E3 ligase CRL4Cdt2 can degrade POLD4/p12 during normal DNA replication and in the presence of DNA damage. POLD4/p12 can also be degraded by the protease µ-calpain, that is involved in calcium-triggered apoptosis.
POLD1/p125 has a NoDS domain that regulates transport to the nucleolus in response to acidosis. Nucleolar transport requires a direct interaction between the p50 subunit and the WRN protein. During DNA damage response, WRN moves out of the nucleolus and thereby releases Polδ. POLD1/p125 has also been shown to interact with PDIP46/SKAR and LMO2.
# Function
## DNA replication
DNA replication is a highly organized process that involves many enzymes and proteins, including several DNA polymerases. The major replicative activity in S phase of cell cycle depends on three DNA polymerases - Polymerase alpha (Polα), Polymerase delta (Polδ), and Polymerase epsilon (Polε). After initiation of DNA synthesis by Polα, Polδ or Polε execute lagging and leading strand synthesis, respectively. These polymerases maintain a very high fidelity, which is ensured by Watson-Crick base pairing and 3'-exonuclease (or the proofreading) activity. Recent studies have contended that Polδ may synthesize the leading strand. How these polymerases function, in relationship with other factors involved in replication, is of great interest as it likely explains the mutational landscape that they produce when defective. Maintenance of replication fidelity is a fine balance between the unique errors by polymerases δ and ε, the equilibrium between proofreading and MMR, and distinction in ribonucleotide processing between the two strands. Extensive studies in yeast models have shown that mutations in the exonuclease domain of Polδ and Polε homologues can cause a mutator phenotype, reviewed in. The single stranded (ss) DNA synthesized during lagging strand synthesis can be targeted by ss-DNA damaging agents as well as is a selective target for APOBEC mutations. DNA-binding proteins that rapidly reassociate post-replication prevent Polδ from repairing errors produced by Polα in the mature lagging strand. Yeast studies have shown that Polδ can proofread Polε errors on the leading strand.
## DNA Repair
POLD1 activity contributes to multiple evolutionarily conserved DNA repair processes, including Mismatch repair (MMR), Translesion synthesis (TLS), Base excision repair (BER), Nucleotide Excision repair (NER) and double-strand break (DSB) repair. POLD1 mediates the post-incision steps in BER, NER and MMR. Polδ interacts with the MMR machinery to support post-replication proofreading of newly synthesized DNA, with cells bearing mutations that inactivate POLD1 and MMR components experiencing elevated mutation rates. As noted above, a Polδ heterotrimer (Polδ3) becomes the dominant oligomeric form of POLD1 and is active during the presence of DNA damage. Polδ3 is less error-prone than (Polδ4), and can discriminate better between mismatched pairs, associated with better proofreading activity: however, it has reduced ability to bypass some base lesions. Instead, Polδ polymerase switching to the specialized polymerase zeta (Polζ) is important for TLS as the substitution of p125 for the Polζ catalytic subunit, p353, permits better bypass activity. In this process, the highly conserved C-terminal domain (CTD) of POLD1/p125 interacts with the CTD domain of Polζ, and the iron clusters within each CTD mediate interactions involving binding to POLD2 that permit polymerase switching during TLS. Some recent studies suggest that a switch from Polδ to Pol lambda (λ) also supports the TLS and repair of oxidative DNA damage like 7,8-Dihydro-8-oxoguanine lesions.
Depletion of POLD1 can halt cell cycle at G1 and G2/M phases in human cells. Cell cycle block in these phases typically indicates presence of DNA damage and activation of DNA damage checkpoints. POLD1 depleted cells are sensitive to inhibition of DNA damage checkpoint kinases ATR and CHK1. In S. pombe, HR mechanisms could restart stalled replication forks by utilizing Polδ strand synthesis activity, but such nonallelic HR-mediated restart is very error prone potentially leading to increased genomic instability. Polδ structurally and functionally interacts with the WRN protein, and WRN recruits Polδ to the nucleolus. The WRN gene is mutated in Werner syndrome (an autosomal recessive disorder) leading to accelerated aging and increased genetic instability. The interaction with WRN increases the processivity of Polδ in a PCNA-independent manner. Through these interactions WRN directly impacts DNA replication-repair and assists in Polδ-mediated synthesis.
# Clinical significance
## Cancer
DNA repair proteins have been shown to be important in human diseases including cancer. For example, germline mutations in DNA repair proteins involved in MMR (MSH2, MLH1, MSH6, and PMS2) have been described in Lynch syndrome (LS), which is characterized by the presence of microsatellite instability (MSI). More recently, germline mutations have been reported in the exonuclease domains of POLD1 and POLE, the catalytic subunit of Polε. These mutations are associated with oligo-adenomatous polyposis, early-onset colorectal cancer (CRC), endometrial cancer (EDMC), breast cancer, and brain tumors.( reviewed in) Most of the reported POLD1 mutations linked to cancer are present in the exonuclease domain. In contrast to LS, the POLD1 mutated tumors are microsatellite stable. Some data suggests the idea that POLD1 tumors are associated with driver mutations in genes including APC and KRAS. The POLD1 missense mutation p. S478N, in the exonuclease domain, has been validated as damaging and pathogenic. Other POLD1 variants have been clinically identified which have been predicted to be damaging and are currently under further investigation (e.g., p. D316H, p. D316G, p. R409W, p. L474P and p. P327L).
In pediatric patients, double hit mutations in POLD1 or POLE and biallelic mismatch repair deficiency (bMMRD), leads to ultra-hypermutated tumor phenotypes. Such phenotypes as ultra-hypermutation in tumors may indicate better response to newer cancer therapeutics in development, although this needs direct evaluation for POLD1. Bouffet et al. report two siblings with bMMRD- glioblastoma multiforme who have somatic mutations in POLE (P436H in one, S461P in the other), and showed a durable response to a clinical trial with the anti-programmed death-1 inhibitor nivolumab. POLD1 mutations have been studied in cell lines and mouse models. For example, a homozygous Polδ mutation in mice that disrupts enzymatic function leads to highly elevated cancer incidence.
## MDPL
Damaging mutations in POLD1 have also been observed in patients with a syndrome known as mandibular hypoplasia, deafness, and progeroid features with lipodystrophy (MDPL/MDP) syndrome (#615381 in the Online Mendelian Inheritance in Man (OMIM) database). This is a very rare syndrome, and few studies describing mutations have been reported. The mutations that have been observed are in the regions that affect the exonuclease domain and polymerase domains. Five unrelated de novo cases have been described with the same heterozygous variant, c.1812_1814delCTC p.Ser605del (rs398122386). S605 is in the highly conserved motif A of the polymerase active site. This variant does not inhibit the DNA binding activity but impacts catalysis. Another variant has been reported in a separate patient (p.R507C). This variant is located in the highly conserved ExoIII domain and has not been completely characterized as yet.
POLD1 Ser605del and R507C variants have also been identified in a subset of patients with atypical Werner’s syndrome (AWS). After molecular testing, these patients were reclassified as MDPL/MDP patients. MDPL/MDP, AWS and Werner’s syndrome all present with progeria. A first example of germline transmission was observed in a mother and son with the Ser605del mutation. Recently, two independent studies identified patients with the same homozygous splice variant in POLE1, the catalytic subunit of Polε. One presented with a phenotype of facial dysmorphism, immunodeficiency, livedo, and short stature (also knowns as the FILS syndrome). The second one presented with more severe symptoms. These cases join a growing number of developmental defects associated with inherited mutations targeting the function of polymerase genes.
Age-dependent downregulation of POLD1 has been observed. although no clinical significance has been associated with this phenotype as yet. Studies are also underway to understand if there is a relation between these pathologies or these mutations and a predisposition to cancer. Currently proposed mechanisms by which POLD1 defects are pathogenic focus on the idea of replication defects leading to genomic instability and checkpoint activation, ultimately leading to cell death or cellular senescence. Alternatively, Polδ is associated with lamins and the nuclear envelope during G1/S arrest or early S phase; mutations in lamins cause nuclear envelope-related lipodystrophies with phenotypes similar to MDPL/MDP and Werner’s syndrome.
## Cancer risk assessment and commercial testing
The hereditary colorectal cancers (CRCs) associated with mutations in the proofreading ability of POLD1 and POLE are sometimes termed as “polymerase proofreading associated polyposis” (PPAP), (although at least one study has identified POLD1 mutations associated with non-polyposis CRC). POLD1 mutations have also been associated with an increased cancer predisposition of endometrial cancer. A recent study has suggested guidelines for genetic testing for POLD1 mutations which include: 1) Occurrence of 20-100 adenomas, and 2) Family history that meets the Amsterdam II criteria for colorectal and endometrial cancers. Current clinical testing guidelines for families with mutations in POLD1/POLE include colonoscopies (every 1–2 years), gastroduodenoscopies (every 3 years) starting early (20-25), possibility for brain tumors and endometrial cancer screening (beginning at 40 for female carriers). Currently studies are underway to determine the exact cancer risk from specific POLD1 mutations. Current data suggest that mutations in this gene are highly penetrant. Another recent study showed that mutations affecting Polδ and Polε mutations can co-occur along with MMR mutations. This suggests panel gene testing should include MMR and Pol genes even in patients with MSI.
There are several options for commercial diagnostic testing for mutations in POLD1. Genetic testing typically includes POLD1 coding exons (26) and at least 20 bases into the adjacent non-coding regions. For families with known mutations, single site testing is also available to confirm the presence of a mutation. The availability of these genetic tests has opened up new possibilities for cancers previously classified as genetically undefined colorectal cancers or colorectal cancer type “X”. Resources for clinical testing for MDPL/MDP have also been developed.
# Notes | POLD1
The gene polymerase delta 1 (POLD1) encodes the large, POLD1/p125, catalytic subunit of the DNA polymerase delta (Polδ) complex.[1][2] The Polδ enzyme is responsible for synthesizing the lagging strand of DNA, and has also been implicated in some activities at the leading strand (Figure 1). The POLD1/p125 subunit encodes both DNA polymerizing and exonuclease domains, which provide the protein an important second function in proofreading to ensure replication accuracy during DNA synthesis, and in a number of types of replication-linked DNA repair following DNA damage. Germline mutations impairing activity of POLD1 have been implicated in several types of hereditary cancer, in some sporadic cancers, and in a developmental syndrome of premature aging, Mandibular hypoplasia, Deafness, and Progeroid features and Lipodystrophy (MDPL/MDP syndrome). Studies of POLD1 emphasize the importance of maintaining genomic stability to limit tumorigenesis. It is currently unclear whether the enhanced tumorigenesis associated with POLD1 defects is the result of increased base substitutions or due to fork collapse and production of DNA double strand breaks (DSBs).[2][3] Recent reviews have addressed important functions of POLD1 and Polδ.[2][3]
# Discovery
The first DNA polymerase, DNA polymerase I, was discovered by Arthur Kornberg and his colleagues in 1956,[4] reviewed in.[5] In 1976, Byrnes et al. discovered a third DNA polymerase activity in mammalian cells that was called polymerase delta (δ).[6] It was purified from rabbit erythroid hyperplastic bone marrow and described as a DNA polymerase that possessed an intrinsic 3’ to 5’ exonuclease activity. A 3’-5’ exonuclease proofreading function for DNA polymerases (E. coli) had first been described 4 years earlier by Kornberg and Brutlag,[7] reviewed in.[8] The human DNA Polδ is a heterotetramer. The four subunits are: (POLD1/ p125), (POLD3/ p66), (POLD2/ p50) and (POLD4/ p12), with the alternative names reflecting the molecular weights expressed in kilodaltons (kDa). The polymerase catalytic subunit was identified as the 125 kDa polypeptide by activity staining in 1991.[9] Several groups independently cloned the human and murine POLD1 cDNAs.[1][10][11] Following its purification from various sources including calf thymus, human placenta, and HeLa cells,[12][13][14][15][16] its activity was implicated in DNA repair.[17][18]
# Gene
Polymerase (DNA) delta 1, catalytic subunit and POLD1 are the name and gene symbol approved by the Human Genome Organization (HUGO) Gene Nomenclature Committee (HGNC).[19] POLD1 is also known as CDC2, MDPL, POLD, and CRCS10), is ~34 kb long and its cytogenetic location is chromosome 19[20] q13.33.[21] The precise location, in the GRCh38.p2 assembly, is from base pair 50,384,290 to base pair 50,418,018 on chromosome 19.[22] The mouse orthologue maps to mouse chromosome 7.[23] In humans, the major POLD1 transcript (NM_002691.3) contains 27 exons and translates into the 1107 amino acids of the p125 or A subunit. A longer isoform has been reported with a 26 amino acid in-frame insertion after amino acid 592 (NP_001295561.1). A pseudogene (LOC100422453) has been reported on the long arm of chromosome 6.[22] Table 1 provides gene names and chromosomal locations for the various subunits of Polδ in humans, mice, budding yeast (S. cerevisiae) and fission yeast (S. pombe).
The POLD1 gene promoter is regulated via the cell cycle machinery and mRNA expression of POLD1 reaches a peak in late G1/S phase during DNA replication.[24] The POLD1 promoter is G/C-rich and has no TATA box. The transcription of this GC box-containing promoter is regulated by Sp1 and Sp1-related transcription factors such as Sp3, with their binding mediated via 11-bp repeat binding sequences.[25][26] The POLD1 promoter contains an E2F-like sequence located near the major transcription start site.[26] Another regulatory element, the cell cycle element/cell cycle genes homology region (CDE/CHR), located downstream of the start site is important for POLD1 transcription in G2/M phase by E2F1 and p21 proteins.[27][28] P53 regulates POLD1 transcription by indirect p21-dependent activation of a p53-p21-DREAM-CDE/CHR pathway.[29] One study has reported that the p53 tumor suppressor protein competes with Sp1 for binding to the POLD1 promoter.[25] A microRNA (miR), miR-155, downregulates POLD1 indirectly by suppressing the transcription factor FOXO3a,[30] which has putative binding sites in the POLD1 promoter (RTMAAYA; response element).[31]
# Protein
POLD1/p125 has a common B-family fold, similar to other DNA polymerases (Polα and ε).[33] Human POLD1/p125 has a putative nuclear localization signal at the N-terminal end (residues 4-19).[20] Residues 304-533 contain the exonuclease domain (Figure 2) while residues 579-974 contain the polymerase domain. The exonuclease domain is a DEDDy-type DnaQ-like domain common to the B-DNA polymerase family.[34] This domain has a beta hairpin structure that helps in switching between the polymerase and exonuclease active sites in case of nucleotide misincorporation.
Motifs A and C, which are the most conserved of the polymerase domain. These have 2 catalytic aspartates, in motif A (DXXLYPS, D602) and motif C (DTDS, D757) that bind calcium at the active site. Motif A has 11 amino acids that are important in nucleotide incorporation and formation of the phosphodiester bond.
Tyrosine Y701 functions similarly to tyrosine Y567 in the RB69 bacteriophage orthologue as the sugar steric gate that prevents ribonucleotide incorporation.[35] An LXCXE motif (711 to 715) mediates binding to pRB during the G1 phase of cell cycle.[36] The polymerase domain also has a highly conserved KKRY motif (residues 806 to 809) which is important for the binding and catalytic function.[37] POLD1 can be targeted to the nucleolus upon acidification via a nucleolar detention sequence (NoDS) motif represented by small sequence motifs dispersed throughout the protein coding region.[38][39][40] The C-terminal domain has two conserved cysteine-rich metal-binding motifs (CysA and CysB) (from 1012 and 1083) required for Proliferating Cell Nuclear Antigen (PCNA) binding and recruitment of accessory subunits respectively.[41] CysB coordinates an [4Fe-4S] cluster added through Cytosolic Iron-sulfur protein Assembly (CIA), which requires the function of the mitochondrial Iron Sulfur Cluster (ISC) assembly machinery.[42] The maturation process is mediated by the core targeting complex CIA1-CIA2B/FAM96B-MMS19, which interacts with the apoprotein to ensure specific Fe-S cluster insertion.[43][44]
Binding and association studies have shown that POLD2 is tightly associated with POLD1; POLD3 and POLD2 interact with each other and POLD4 interacts with both POLD1 and POLD2.[47][48] Polδ heterotetramer reconstituted by coexpression of subunits in Sf9 cells had properties were similar to Polδ purified from the calf thymus, and the complete holoenzyme was very strongly stimulated by PCNA.[49] Numerous studies have shown that while POLD1 possesses both the polymerase and the 3’-5’ exonuclease proofreading activity, the other subunits increase these activities, DNA binding abilities, and functionally important interactions with PCNA and its clamp loader Replication Factor C (RFC). The DNA Polδ holoenzyme is often considered to include PCNA and RFC as well as the four subunits of the polymerase complex (Figure 1).
A number of other studies and screens have identified additional interaction partners relevant to functions in DNA replication and repair. Figure 3 shows a matrix of established and putative interactions during replication and repair which can be further accessed through[50] and.[51] A website at Vanderbilt University provides additional interaction on important POLD1 protein structure and various classes of gene and protein interaction, based on criteria such as co-occurrence in a complex, direct physical interaction, regulatory relationship, and co-expression.[52]
## Expression and regulation
The POLD1/P125 protein is expressed ubiquitously across a panel of human tissues with high levels in the heart and lung tissues.[56] The subcellular localization of POLD1/p125 is predominantly in the nucleus and nucleoplasm.[57]
A reduction in POLD1/p125 has been observed in senescent human skin fibroblasts and in lymphocytes from an elderly population.[58][59] POLD1/p125 expression is epigenetically regulated in response to DNA damage.[60] Other studies have also shown that POLD1/p125 expression is regulated by miR-155,[30] p53[25] and by the long non-coding RNA, PVT1.[61] In the presence of DNA damage or replication stress (UV light, methyl methanesulfonate, hydroxyurea or aphidicolin), the POLD4/p12 subunit is rapidly degraded. The catalytic activities of p125 are different whether it is in the heterotetramer (Polδ4, with p12 [62][63]) or in the heterotrimer (Polδ3, without p12).[64] The production of the heterotrimer depends on p12 degradation by the E3 ligase RNF8, a protein involved in DSBs repair and possibly homologous recombination (HR).[65] In addition, the E3 ligase CRL4Cdt2 can degrade POLD4/p12 during normal DNA replication and in the presence of DNA damage.[66] POLD4/p12 can also be degraded by the protease µ-calpain, that is involved in calcium-triggered apoptosis.[67][68]
POLD1/p125 has a NoDS domain that regulates transport to the nucleolus in response to acidosis.[40] Nucleolar transport requires a direct interaction between the p50 subunit and the WRN protein.[69] During DNA damage response, WRN moves out of the nucleolus and thereby releases Polδ.[70][71] POLD1/p125 has also been shown to interact with PDIP46/SKAR[72] and LMO2.[73][74]
# Function
## DNA replication
DNA replication is a highly organized process that involves many enzymes and proteins, including several DNA polymerases. The major replicative activity in S phase of cell cycle depends on three DNA polymerases - Polymerase alpha (Polα), Polymerase delta (Polδ), and Polymerase epsilon (Polε). After initiation of DNA synthesis by Polα, Polδ or Polε execute lagging and leading strand synthesis, respectively.[75] These polymerases maintain a very high fidelity, which is ensured by Watson-Crick base pairing and 3'-exonuclease (or the proofreading) activity.[76] Recent studies have contended that Polδ may synthesize the leading strand.[76][77][78][79][80] How these polymerases function, in relationship with other factors involved in replication, is of great interest as it likely explains the mutational landscape that they produce when defective. Maintenance of replication fidelity is a fine balance between the unique errors by polymerases δ and ε,[81] the equilibrium between proofreading and MMR, and distinction in ribonucleotide processing between the two strands.[32] Extensive studies in yeast models have shown that mutations in the exonuclease domain of Polδ and Polε homologues can cause a mutator phenotype, reviewed in.[82] The single stranded (ss) DNA synthesized during lagging strand synthesis can be targeted by ss-DNA damaging agents as well as is a selective target for APOBEC mutations.[83] DNA-binding proteins that rapidly reassociate post-replication prevent Polδ from repairing errors produced by Polα in the mature lagging strand.[84] Yeast studies have shown that Polδ can proofread Polε errors on the leading strand.[85]
## DNA Repair
POLD1 activity contributes to multiple evolutionarily conserved DNA repair processes, including Mismatch repair (MMR), Translesion synthesis (TLS), Base excision repair (BER), Nucleotide Excision repair (NER) and double-strand break (DSB) repair.[2] POLD1 mediates the post-incision steps in BER, NER and MMR.[2] Polδ interacts with the MMR machinery to support post-replication proofreading of newly synthesized DNA,[86] with cells bearing mutations that inactivate POLD1 and MMR components experiencing elevated mutation rates.[87][88] As noted above, a Polδ heterotrimer (Polδ3) becomes the dominant oligomeric form of POLD1 and is active during the presence of DNA damage. Polδ3 is less error-prone than (Polδ4), and can discriminate better between mismatched pairs, associated with better proofreading activity: however, it has reduced ability to bypass some base lesions.[70][89] Instead, Polδ polymerase switching to the specialized polymerase zeta (Polζ) is important for TLS as the substitution of p125 for the Polζ catalytic subunit, p353, permits better bypass activity.[2] In this process, the highly conserved C-terminal domain (CTD) of POLD1/p125 interacts with the CTD domain of Polζ, and the iron clusters within each CTD mediate interactions involving binding to POLD2 that permit polymerase switching during TLS.[90] Some recent studies suggest that a switch from Polδ to Pol lambda (λ) also supports the TLS and repair of oxidative DNA damage like 7,8-Dihydro-8-oxoguanine lesions.[91]
Depletion of POLD1 can halt cell cycle at G1 and G2/M phases in human cells.[92] Cell cycle block in these phases typically indicates presence of DNA damage and activation of DNA damage checkpoints. POLD1 depleted cells are sensitive to inhibition of DNA damage checkpoint kinases ATR and CHK1.[93] In S. pombe, HR mechanisms could restart stalled replication forks by utilizing Polδ strand synthesis activity, but such nonallelic HR-mediated restart is very error prone potentially leading to increased genomic instability.[94] Polδ structurally and functionally interacts with the WRN protein, and WRN recruits Polδ to the nucleolus.[69] The WRN gene is mutated in Werner syndrome (an autosomal recessive disorder) leading to accelerated aging and increased genetic instability. The interaction with WRN increases the processivity of Polδ in a PCNA-independent manner.[95] Through these interactions WRN directly impacts DNA replication-repair and assists in Polδ-mediated synthesis.
# Clinical significance
## Cancer
DNA repair proteins have been shown to be important in human diseases including cancer. For example, germline mutations in DNA repair proteins involved in MMR (MSH2, MLH1, MSH6, and PMS2) have been described in Lynch syndrome (LS), which is characterized by the presence of microsatellite instability (MSI).[96] More recently, germline mutations have been reported in the exonuclease domains of POLD1 and POLE, the catalytic subunit of Polε. These mutations are associated with oligo-adenomatous polyposis, early-onset colorectal cancer (CRC), endometrial cancer (EDMC), breast cancer, and brain tumors.([97][98][99][100][101] reviewed in[3]) Most of the reported POLD1 mutations linked to cancer are present in the exonuclease domain.[3][97][98][102][103][104] In contrast to LS, the POLD1 mutated tumors are microsatellite stable. Some data suggests the idea that POLD1 tumors are associated with driver mutations in genes including APC and KRAS.[97] The POLD1 missense mutation p. S478N, in the exonuclease domain, has been validated as damaging and pathogenic.[97] Other POLD1 variants have been clinically identified which have been predicted to be damaging and are currently under further investigation (e.g., p. D316H, p. D316G, p. R409W, p. L474P and p. P327L).[98][99][100]
In pediatric patients, double hit mutations in POLD1 or POLE and biallelic mismatch repair deficiency (bMMRD), leads to ultra-hypermutated tumor phenotypes.[105][106][107] Such phenotypes as ultra-hypermutation in tumors may indicate better response to newer cancer therapeutics in development, although this needs direct evaluation for POLD1.[108][109][110][111][112][113] Bouffet et al. report two siblings with bMMRD- glioblastoma multiforme who have somatic mutations in POLE (P436H in one, S461P in the other), and showed a durable response to a clinical trial with the anti-programmed death-1 inhibitor nivolumab. POLD1 mutations have been studied in cell lines [114][115][116][117] and mouse models. For example, a homozygous Polδ mutation in mice that disrupts enzymatic function leads to highly elevated cancer incidence.[118]
## MDPL
Damaging mutations in POLD1 have also been observed in patients with a syndrome known as mandibular hypoplasia, deafness, and progeroid features with lipodystrophy (MDPL/MDP) syndrome (#615381 in the Online Mendelian Inheritance in Man (OMIM) database).[56][119][120] This is a very rare syndrome, and few studies describing mutations have been reported. The mutations that have been observed are in the regions that affect the exonuclease domain and polymerase domains.[56][119] Five unrelated de novo cases have been described with the same heterozygous variant, c.1812_1814delCTC p.Ser605del (rs398122386). S605 is in the highly conserved motif A of the polymerase active site. This variant does not inhibit the DNA binding activity but impacts catalysis. Another variant has been reported in a separate patient (p.R507C).[119] This variant is located in the highly conserved ExoIII domain and has not been completely characterized as yet.
POLD1 Ser605del and R507C variants have also been identified in a subset of patients with atypical Werner’s syndrome (AWS). After molecular testing, these patients were reclassified as MDPL/MDP patients. MDPL/MDP, AWS and Werner’s syndrome all present with progeria.[121] A first example of germline transmission was observed in a mother and son with the Ser605del mutation.[122] Recently, two independent studies identified patients with the same homozygous splice variant in POLE1, the catalytic subunit of Polε. One presented with a phenotype of facial dysmorphism, immunodeficiency, livedo, and short stature (also knowns as the FILS syndrome).[123] The second one presented with more severe symptoms.[124] These cases join a growing number of developmental defects associated with inherited mutations targeting the function of polymerase genes.
Age-dependent downregulation of POLD1 has been observed.[59] although no clinical significance has been associated with this phenotype as yet. Studies are also underway to understand if there is a relation between these pathologies or these mutations and a predisposition to cancer. Currently proposed mechanisms by which POLD1 defects are pathogenic focus on the idea of replication defects leading to genomic instability and checkpoint activation, ultimately leading to cell death or cellular senescence. Alternatively, Polδ is associated with lamins and the nuclear envelope during G1/S arrest or early S phase; mutations in lamins cause nuclear envelope-related lipodystrophies with phenotypes similar to MDPL/MDP and Werner’s syndrome.[125]
## Cancer risk assessment and commercial testing
The hereditary colorectal cancers (CRCs) associated with mutations in the proofreading ability of POLD1 and POLE are sometimes termed as “polymerase proofreading associated polyposis” (PPAP), (although at least one study has identified POLD1 mutations associated with non-polyposis CRC).[97][98][100][102][103] POLD1 mutations have also been associated with an increased cancer predisposition of endometrial cancer.[97][100][101] A recent study has suggested guidelines for genetic testing for POLD1 mutations which include: 1) Occurrence of 20-100 adenomas, and 2) Family history that meets the Amsterdam II criteria for colorectal and endometrial cancers.[99] Current clinical testing guidelines for families with mutations in POLD1/POLE include colonoscopies (every 1–2 years), gastroduodenoscopies (every 3 years) starting early (20-25), possibility for brain tumors and endometrial cancer screening (beginning at 40 for female carriers).[99] Currently studies are underway to determine the exact cancer risk from specific POLD1 mutations. Current data suggest that mutations in this gene are highly penetrant. Another recent study showed that mutations affecting Polδ and Polε mutations can co-occur along with MMR mutations.[106] This suggests panel gene testing should include MMR and Pol genes even in patients with MSI.
There are several options for commercial diagnostic testing for mutations in POLD1.[126] Genetic testing typically includes POLD1 coding exons (26) and at least 20 bases into the adjacent non-coding regions. For families with known mutations, single site testing is also available to confirm the presence of a mutation.[126] The availability of these genetic tests has opened up new possibilities for cancers previously classified as genetically undefined colorectal cancers or colorectal cancer type “X”.[101] Resources for clinical testing for MDPL/MDP have also been developed.[127]
# Notes | https://www.wikidoc.org/index.php/POLD1 | |
b1975d262036657b54f8a676a452ea326957e5ff | wikidoc | POLG2 | POLG2
DNA polymerase subunit gamma-2, mitochondrial is a protein that in humans is encoded by the POLG2 gene. The POLG2 gene encodes a 55 kDa accessory subunit protein that imparts high processivity and salt tolerance to the catalytic subunit of DNA polymerase gamma, encoded by the POLG gene. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.
# Structure
POLG2 is located on the q arm of chromosome 17 in position 23.3 and has 8 exons. POLG2, the protein encoded by this gene, contains a phosphoserine modified residue at p. 38 and a transit peptide. Its structure consists of 25 beta strands, 21 alpha helixes, and 8 turns.
# Function
POLG2 encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding, stimulates polymerase and exonuclease activity, and promotes processive DNA synthesis.
## Catalytic activity
Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)
# Clinical significance
Mutations in POLG2 have been associated with progressive external ophthalmoplegia with mitochondrial DNA deletions. This disease results in progressive weakness of ocular muscles and levator muscle of the upper eyelid and patients with it may also manifest skeletal myopathy, ragged-red fibers and atrophy shown on muscle biopsy, cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. This mutlisystemic disease has been linked to a G451E mutation that disrupts the DNA polymerase gamma subunits.
In patients with chronic hepatitis C, those carrying the DDX5 minor allele or DDX5-POLG2 haplotypes are thought to be at an increased risk of advanced fibrosis. It is important to note, however, that those carrying the CPT1A minor allele are believed to be at a decreased risk.
# Interactions
POLG2 has been shown to have 32 binary protein-protein interactions including 19 co-complex interactions. POLG2 appears to interact with POLG. | POLG2
DNA polymerase subunit gamma-2, mitochondrial is a protein that in humans is encoded by the POLG2 gene. The POLG2 gene encodes a 55 kDa accessory subunit protein that imparts high processivity and salt tolerance to the catalytic subunit of DNA polymerase gamma, encoded by the POLG gene.[1][2] Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.[3]
# Structure
POLG2 is located on the q arm of chromosome 17 in position 23.3 and has 8 exons.[3] POLG2, the protein encoded by this gene, contains a phosphoserine modified residue at p. 38 and a transit peptide. Its structure consists of 25 beta strands, 21 alpha helixes, and 8 turns.[4][5]
# Function
POLG2 encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding, stimulates polymerase and exonuclease activity, and promotes processive DNA synthesis.[3][4][5]
## Catalytic activity
Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1)[4][5]
# Clinical significance
Mutations in POLG2 have been associated with progressive external ophthalmoplegia with mitochondrial DNA deletions. This disease results in progressive weakness of ocular muscles and levator muscle of the upper eyelid and patients with it may also manifest skeletal myopathy, ragged-red fibers and atrophy shown on muscle biopsy, cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. This mutlisystemic disease has been linked to a G451E mutation that disrupts the DNA polymerase gamma subunits.[4][5][6]
In patients with chronic hepatitis C, those carrying the DDX5 minor allele or DDX5-POLG2 haplotypes are thought to be at an increased risk of advanced fibrosis. It is important to note, however, that those carrying the CPT1A minor allele are believed to be at a decreased risk.[7]
# Interactions
POLG2 has been shown to have 32 binary protein-protein interactions including 19 co-complex interactions. POLG2 appears to interact with POLG.[8] | https://www.wikidoc.org/index.php/POLG2 | |
72c567074dd42c0b44975f38e5b2dfaa9cfebae9 | wikidoc | PORCN | PORCN
PORCN (porcupine homolog – Drosophila) is a human gene.
The protein is homologous to other membrane-bound O-acyltransferases.
# Function
The protein encoded by this gene is an endoplasmic reticulum transmembrane protein involved in processing of wingless proteins such as WNT7A.
# Clinical significance
Mutations in this gene are associated with focal dermal hypoplasia.
Mutations in PORCN are associated to Goltz-Gorlin syndrome .
# Ligands
## Inhibitors
- WNT974 (LGK-974) - 1243244-14-5, researched for anti-cancer effects in Wnt-pathway sensitive tumours. Also investigated for influencing cardiac tissue remodelling following infarction.
IWP (1-4)
RXC004 | PORCN
PORCN (porcupine homolog – Drosophila) is a human gene.[1][2]
The protein is homologous to other membrane-bound O-acyltransferases.
# Function
The protein encoded by this gene is an endoplasmic reticulum transmembrane protein involved in processing of wingless proteins such as WNT7A.[2]
# Clinical significance
Mutations in this gene are associated with focal dermal hypoplasia.[3]
Mutations in PORCN are associated to Goltz-Gorlin syndrome .[4]
# Ligands
## Inhibitors
- WNT974 (LGK-974) - 1243244-14-5, researched for anti-cancer effects in Wnt-pathway sensitive tumours.[5] Also investigated for influencing cardiac tissue remodelling following infarction.[6]
IWP (1-4)
RXC004 | https://www.wikidoc.org/index.php/PORCN | |
869bf64f8683e1dbfd901e2e937f0718cb5ca50e | wikidoc | POTEB | POTEB
POTE ankyrin domain family, member B is a protein in humans that is encoded by the POTEB gene..It is most likely involved in mediating protein-protein interaction via its 5 ankyrin domains. POTEB is most probably aids in intracellular signaling, but is not likely to be a secreted or nuclear protein. POTEB's function is likely to be regulated via 17 potential phosphorylation sites. There is currently no evidence to suggest that POTEB has nuclear localization signals.
# Gene
POTEB is located at 15q11.2 on chromosome 15 in humans and is transcribed from the reverse DNA strand. POTEB is also known as POTEB3 and POTE15. The POTEB gene is 47,547 base pairs in length and is composed of 11 exons.
# mRNA
The POTEB gene can be transcribed to create four potential mRNAs. However, only one of these mRNAs, possessing all 11 exons, is capable of being translated to the POTEB protein. The three other transcripts do not encode proteins.
# Protein
The POTEB protein is composed of 544 amino acids and, according to bioinformatic analyses, has a molecular weight of 61.7 kDa. It has an isoelectric point of 5.68. Its most common amino acids are leucine and glutamic acid, which account for 11% and 10.3% of the protein respectively. However, this is normal for human proteins. POTEB is most likely a cytoplasmic protein that is phosphorylated at 17 serines, threonines, and tyrosines located throughout the length of the protein, but concentrated at the C-terminus of the protein. Its secondary structure is mainly five helical ankyrin repeat domains, which contain the TALHL motif. There is also one myristoylation site on the protein, close to the N-terminus.
# Expression
POTEB is expressed at high levels in the human prostate, ovary, and testes. However, there is also evidence to show that it is expressed at low levels in embryonic stem cells, the nasopharyngeal region, and in breast tissue. In embryonic stem cells, differentiation is likely to turn off the expression of POTEB while in breast cancer, triple negative cells are found to have no POTEB expression suggesting a role in cancer-activated pathways.
Some studies have used POTEB probes to study the expression of POTEB in the human brain. However, the only region with notable POTEB expression is the cerebellar cortex, responsible for motor function and some cognitive functions.
# Regulation of Expression
POTEB expression is likely regulated by E-box binding factors and Krueppel-like transcription factors, along with nuclear factor kappa B (NF-κB) transcription factors.
POTEB expression could be regulated by the binding of transcription factors to intron 1 of the pre-mRNA, leading to the production of a truncated mRNA which is not translated. Alternatively, POTEB expression could be downregulated by the formation of stem loops close to the start codon. There are no known ubiquitination sites in POTEB that could aid in regulating POTEB function and stability.
# Function
POTEB is most likely involved in mediating protein-protein interaction via its 5 ankyrin domains. POTEB is most probably aids in intracellular signaling, but is not likely to be a secreted or nuclear protein as it is unlikely to contain nuclear localization signals. POTEB's function is likely to be regulated via 17 potential phosphorylation sites which determine how the ankyrin domains interact with other proteins.
## Protein-Protein Interactions
There have been no studies published confirming the interaction of POTEB with other human proteins. However, there is unpublished data suggesting an interaction between POTEB and alpha-1-B glycoproteins, APOBEC1 complementation factors, and alpha-2-macroglobulin. This data is based on affinity capture- mass spectrometry.
# Clinical Significance
POTEB expression is low or completely reduced in triple-negative breast cancer cells when compared to other types of breast cancer cells. This suggests POTEB’s involvement in intracellular signaling pathways that suppress cancer, or in pathways that regulate the normal growth and division of cells.
# Homology
## Paralogs
POTEB has 8 predicted paralogs (According to protein sequence) in humans, with most paralogs being located on different human chromosomes. It is speculated that this large number of paralogs arose from multiple duplication events.
## Orthologs
POTEB orthologs have been found in mammals, birds, reptiles, amphibians, fish, and even in invertebrates such as sea anemones and marine polychaete worms. These orthologs share a similarity with POTEB largely due to the presence of ankyrin repeats, suggesting that ankyrin domain-containing proteins have been conserved over millions of years. POTEB orthologs have not been found in plants, unicellular eukaryotes, bacteria and archaea. | POTEB
POTE ankyrin domain family, member B is a protein in humans that is encoded by the POTEB gene.[1](Prostate, Ovary, Testes Expressed ankyrin domain family member B).It is most likely involved in mediating protein-protein interaction via its 5 ankyrin domains.[2] POTEB is most probably aids in intracellular signaling, but is not likely to be a secreted or nuclear protein.[2] POTEB's function is likely to be regulated via 17 potential phosphorylation sites.[3] There is currently no evidence to suggest that POTEB has nuclear localization signals.[4]
# Gene
POTEB is located at 15q11.2 on chromosome 15 in humans and is transcribed from the reverse DNA strand. POTEB is also known as POTEB3 and POTE15.[5] The POTEB gene is 47,547 base pairs in length and is composed of 11 exons.[5]
# mRNA
The POTEB gene can be transcribed to create four potential mRNAs. However, only one of these mRNAs, possessing all 11 exons, is capable of being translated to the POTEB protein.[6] The three other transcripts do not encode proteins.
# Protein
The POTEB protein is composed of 544 amino acids and, according to bioinformatic analyses, has a molecular weight of 61.7 kDa. It has an isoelectric point of 5.68.[7] Its most common amino acids are leucine and glutamic acid, which account for 11% and 10.3% of the protein respectively.[7] However, this is normal for human proteins. POTEB is most likely a cytoplasmic protein[8] that is phosphorylated at 17 serines, threonines, and tyrosines located throughout the length of the protein,[3] but concentrated at the C-terminus of the protein. Its secondary structure is mainly five helical ankyrin repeat domains, which contain the TALHL motif. There is also one myristoylation site on the protein, close to the N-terminus.[9]
# Expression
POTEB is expressed at high levels in the human prostate, ovary, and testes. However, there is also evidence to show that it is expressed at low levels in embryonic stem cells, the nasopharyngeal region, and in breast tissue.[10][11] In embryonic stem cells, differentiation is likely to turn off the expression of POTEB while in breast cancer, triple negative cells are found to have no POTEB expression suggesting a role in cancer-activated pathways.[11]
Some studies have used POTEB probes to study the expression of POTEB in the human brain. However, the only region with notable POTEB expression is the cerebellar cortex, responsible for motor function and some cognitive functions.[12]
# Regulation of Expression
POTEB expression is likely regulated by E-box binding factors and Krueppel-like transcription factors, along with nuclear factor kappa B (NF-κB) transcription factors.[13]
POTEB expression could be regulated by the binding of transcription factors to intron 1 of the pre-mRNA, leading to the production of a truncated mRNA which is not translated. Alternatively, POTEB expression could be downregulated by the formation of stem loops close to the start codon.[14] There are no known ubiquitination sites in POTEB that could aid in regulating POTEB function and stability.
# Function
POTEB is most likely involved in mediating protein-protein interaction via its 5 ankyrin domains.[2] POTEB is most probably aids in intracellular signaling, but is not likely to be a secreted or nuclear protein[2] as it is unlikely to contain nuclear localization signals.[4] POTEB's function is likely to be regulated via 17 potential phosphorylation sites[3] which determine how the ankyrin domains interact with other proteins.[15]
## Protein-Protein Interactions
There have been no studies published confirming the interaction of POTEB with other human proteins. However, there is unpublished data suggesting an interaction between POTEB and alpha-1-B glycoproteins, APOBEC1 complementation factors, and alpha-2-macroglobulin.[16] This data is based on affinity capture- mass spectrometry.
# Clinical Significance
POTEB expression is low or completely reduced in triple-negative breast cancer cells when compared to other types of breast cancer cells.[11] This suggests POTEB’s involvement in intracellular signaling pathways that suppress cancer, or in pathways that regulate the normal growth and division of cells.
# Homology
## Paralogs
POTEB has 8 predicted paralogs (According to protein sequence) in humans, with most paralogs being located on different human chromosomes.[17][18] It is speculated that this large number of paralogs arose from multiple duplication events.[8]
## Orthologs
POTEB orthologs have been found in mammals, birds, reptiles, amphibians, fish, and even in invertebrates such as sea anemones and marine polychaete worms.[17] These orthologs share a similarity with POTEB largely due to the presence of ankyrin repeats, suggesting that ankyrin domain-containing proteins have been conserved over millions of years. POTEB orthologs have not been found in plants, unicellular eukaryotes, bacteria and archaea.[17] | https://www.wikidoc.org/index.php/POTEB | |
c21f588cb8f2481c22ca730028f147cc337e57c5 | wikidoc | PPIL3 | PPIL3
Peptidyl-prolyl cis-trans isomerase-like 3 is an enzyme that in humans is encoded by the PPIL3 gene.
# Function
This gene encodes a member of the cyclophilin family. Cyclophilins catalyze the cis-trans isomerization of peptidylprolyl imide bonds in oligopeptides. They have been proposed to act either as catalysts or as molecular chaperones in protein-folding events. Transcript variants derived from alternative splicing and/or alternative polyadenylation exist; some of these variants encode different isoforms.
# Model organisms
Model organisms have been used in the study of PPIL3 function. A conditional knockout mouse line called Ppil3tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | PPIL3
Peptidyl-prolyl cis-trans isomerase-like 3 is an enzyme that in humans is encoded by the PPIL3 gene.[1][2]
# Function
This gene encodes a member of the cyclophilin family. Cyclophilins catalyze the cis-trans isomerization of peptidylprolyl imide bonds in oligopeptides. They have been proposed to act either as catalysts or as molecular chaperones in protein-folding events. Transcript variants derived from alternative splicing and/or alternative polyadenylation exist; some of these variants encode different isoforms.[2]
# Model organisms
Model organisms have been used in the study of PPIL3 function. A conditional knockout mouse line called Ppil3tm1b(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[3] Male and female animals underwent a standardized phenotypic screen[4] to determine the effects of deletion.[5][6][7][8] Additional screens performed: - In-depth immunological phenotyping[9] | https://www.wikidoc.org/index.php/PPIL3 | |
b0a0c30d146e135a44c827d2d48acbb452a2e35f | wikidoc | PPM1A | PPM1A
Protein phosphatase 1A is an enzyme that in humans is encoded by the PPM1A gene.
The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding two distinct isoforms have been described.
# Interactions
PPM1A has been shown to interact with Metabotropic glutamate receptor 3.
In 2006, Dr. Feng found that PPM1A can terminate TGF-beta signaling by inactivating Smad3 via dephosphorylation. Smad3 is an essential component of the TGF-beta signalling pathway. | PPM1A
Protein phosphatase 1A is an enzyme that in humans is encoded by the PPM1A gene.[1][2]
The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase dephosphorylates, and negatively regulates the activities of, MAP kinases and MAP kinase kinases. It has been shown to inhibit the activation of p38 and JNK kinase cascades induced by environmental stresses. This phosphatase can also dephosphorylate cyclin-dependent kinases, and thus may be involved in cell cycle control. Overexpression of this phosphatase is reported to activate the expression of the tumor suppressor gene TP53/p53, which leads to G2/M cell cycle arrest and apoptosis. Three alternatively spliced transcript variants encoding two distinct isoforms have been described.[2]
# Interactions
PPM1A has been shown to interact with Metabotropic glutamate receptor 3.[3]
In 2006, Dr. Feng found that PPM1A can terminate TGF-beta signaling by inactivating Smad3 via dephosphorylation. Smad3 is an essential component of the TGF-beta signalling pathway. | https://www.wikidoc.org/index.php/PPM1A | |
4eac3883d1eb21dcee0da6263ac8ebce9f87a102 | wikidoc | PPP5C | PPP5C
Serine/threonine-protein phosphatase 5 is an enzyme that in humans is encoded by the PPP5C gene.
# Model organisms
Model organisms have been used in the study of PPP5C function. A conditional knockout mouse line, called Ppp5ctm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and five significant abnormalities were observed. Homozygous mutant males had decreased body weight, body length and respiratory quotient. Both sexes had increased T cell numbers and a range of skeletal abnormalities identified by radiography.
# Interactions
PPP5C has been shown to interact with ASK1, CRY2 GNA12. and Rac1, | PPP5C
Serine/threonine-protein phosphatase 5 is an enzyme that in humans is encoded by the PPP5C gene.[1][2]
# Model organisms
Model organisms have been used in the study of PPP5C function. A conditional knockout mouse line, called Ppp5ctm1a(EUCOMM)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[14][15][16]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty five tests were carried out on mutant mice and five significant abnormalities were observed.[10] Homozygous mutant males had decreased body weight, body length and respiratory quotient. Both sexes had increased T cell numbers and a range of skeletal abnormalities identified by radiography.[10]
# Interactions
PPP5C has been shown to interact with ASK1,[18] CRY2[19] GNA12.[20] and Rac1,[21] | https://www.wikidoc.org/index.php/PPP5C | |
52a0826fd9499dbd9868a085eca1a802d60ec4a2 | wikidoc | PQBP1 | PQBP1
Polyglutamine-binding protein 1 is a protein that in humans is encoded by the PQBP1 gene.
Polyglutamine binding protein-1 is a highly conserved nuclear protein expressed in mesodermal and nuclear tissues. The molecular roles of PQBP1 in embryonic development are still being understood, but it has been found to function in mRNA splicing, and transcription regulation. Mutations in the PQBP1 gene, which encodes for this protein, have been known to cause X-linked intellectual disabilities (XLID), commonly referred to as Renpenning's syndrome. People who suffer from these disabilities share a common set of symptoms including: microcephaly, shortened stature and impaired intellectual development. There are 11 types of mutations that have been identified, but the most common being frameshift mutations. A knockdown model of the gene in mouse embryo primary neurons revealed a decrease in splicing efficiency and resulted in abnormal gastrulation and neuralation patterning. Attempts at creating both PQBP1 mouse knockout or over expression models have been unsuccessful, often with lethal results. Research indicates that in order to appropriately function, the protein must be expressed within a critical range.
# Function
PQBP1 is a nuclear polyglutamine-binding protein that contains a WW domain (Waragai et al., 1999).
# Interactions
PQBP1 has been shown to interact with:
- POLR2A,
- POU3F2,
- TXNL4A, and
- WBP11. | PQBP1
Polyglutamine-binding protein 1 is a protein that in humans is encoded by the PQBP1 gene.[1][2][3]
Polyglutamine binding protein-1 is a highly conserved nuclear protein expressed in mesodermal and nuclear tissues.[4] The molecular roles of PQBP1 in embryonic development are still being understood, but it has been found to function in mRNA splicing, and transcription regulation.[5] Mutations in the PQBP1 gene, which encodes for this protein, have been known to cause X-linked intellectual disabilities (XLID), commonly referred to as Renpenning's syndrome. People who suffer from these disabilities share a common set of symptoms including: microcephaly, shortened stature and impaired intellectual development.[6] There are 11 types of mutations that have been identified, but the most common being frameshift mutations. A knockdown model of the gene in mouse embryo primary neurons revealed a decrease in splicing efficiency and resulted in abnormal gastrulation and neuralation patterning.[4] Attempts at creating both PQBP1 mouse knockout or over expression models have been unsuccessful, often with lethal results. Research indicates that in order to appropriately function, the protein must be expressed within a critical range.[4]
# Function
PQBP1 is a nuclear polyglutamine-binding protein that contains a WW domain (Waragai et al., 1999).[supplied by OMIM][7]
# Interactions
PQBP1 has been shown to interact with:
- POLR2A,[8]
- POU3F2,[3]
- TXNL4A,[9] and
- WBP11.[9][10] | https://www.wikidoc.org/index.php/PQBP1 | |
0d94b96cfd66b1d343b13637813ad8f67c13ca19 | wikidoc | PRAME | PRAME
Melanoma antigen preferentially expressed in tumors is a protein that in humans is encoded by the PRAME gene.
# Function
This gene encodes an antigen that is predominantly expressed in human melanomas and that is recognized by cytolytic T lymphocytes. It is not expressed in normal tissues, except testis. This expression pattern is similar to that of other CT antigens, such as MAGE, BAGE and GAGE. However, unlike these other CT antigens, this gene is also expressed in acute leukemias. Five alternatively spliced transcript variants encoding the same protein have been observed for this gene.
PRAME can inhibit retinoic acid signaling and retinoic acid mediated differentiation and apoptosis.
# Model organisms
Model organisms have been used in the study of PRAME function. A conditional knockout mouse line called Prametm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | PRAME
Melanoma antigen preferentially expressed in tumors is a protein that in humans is encoded by the PRAME gene.[1][2][3]
# Function
This gene encodes an antigen that is predominantly expressed in human melanomas and that is recognized by cytolytic T lymphocytes. It is not expressed in normal tissues, except testis. This expression pattern is similar to that of other CT antigens, such as MAGE, BAGE and GAGE. However, unlike these other CT antigens, this gene is also expressed in acute leukemias. Five alternatively spliced transcript variants encoding the same protein have been observed for this gene.[3]
PRAME can inhibit retinoic acid signaling and retinoic acid mediated differentiation and apoptosis.[4]
# Model organisms
Model organisms have been used in the study of PRAME function. A conditional knockout mouse line called Prametm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[5] Male and female animals underwent a standardized phenotypic screen[6] to determine the effects of deletion.[7][8][9][10] Additional screens performed: - In-depth immunological phenotyping[11] | https://www.wikidoc.org/index.php/PRAME | |
74a0e7f136ba44baef0be3d65057dfafcfda2c20 | wikidoc | PRDM1 | PRDM1
PR domain zinc finger protein 1 also known as BLIMP-1 is a protein that in humans is encoded by the PRDM1 gene. BLIMP-1 acts as a repressor of beta-interferon (β-IFN) gene expression. The protein binds specifically to the PRDI (positive regulatory domain I element) of the β-IFN gene promoter. Transcription of this gene increases upon virus induction.
# Function
The increased expression of the Blimp-1 protein in B lymphocytes, T lymphocytes, NK cell and other immune system cells leads to an immune response through proliferation and differentiation of antibody secreting plasma cells. Blimp-1 is also considered a 'master regulator' of hematopoietic stem cells.
Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. The genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.
# Second cancers after radiation treatment
A genome-wide association study has identified two genetic variations near the PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment for Hodgkin lymphoma. | PRDM1
PR domain zinc finger protein 1 also known as BLIMP-1 is a protein that in humans is encoded by the PRDM1 gene.[1][2] BLIMP-1 acts as a repressor of beta-interferon (β-IFN) gene expression. The protein binds specifically to the PRDI (positive regulatory domain I element) of the β-IFN gene promoter. Transcription of this gene increases upon virus induction.[2]
# Function
The increased expression of the Blimp-1 protein in B lymphocytes, T lymphocytes, NK cell and other immune system cells leads to an immune response through proliferation and differentiation of antibody secreting plasma cells. Blimp-1 is also considered a 'master regulator' of hematopoietic stem cells.[3][4]
Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. The genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.[5]
# Second cancers after radiation treatment
A genome-wide association study has identified two genetic variations near the PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment for Hodgkin lymphoma.[6] | https://www.wikidoc.org/index.php/PRDM1 | |
d26fd9c090594febebd793ec027db205594700ea | wikidoc | PRDM2 | PRDM2
PR domain zinc finger protein 2 is a protein that in humans is encoded by the PRDM2 gene.
# Function
This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can bind to retinoblastoma protein, estrogen receptor, and the TPA-responsive element (MTE) of the heme-oxygenase-1 gene. Although the functions of this protein have not been fully characterized, it may (1) play a role in transcriptional regulation during neuronal differentiation and pathogenesis of retinoblastoma, (2) act as a transcriptional activator of the heme-oxygenase-1 gene, and (3) be a specific effector of estrogen action. Three transcript variants encoding different isoforms have been found for this gene.
# Interactions
PRDM2 has been shown to interact with Estrogen receptor alpha and Retinoblastoma protein. | PRDM2
PR domain zinc finger protein 2 is a protein that in humans is encoded by the PRDM2 gene.[1][2]
# Function
This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can bind to retinoblastoma protein, estrogen receptor, and the TPA-responsive element (MTE) of the heme-oxygenase-1 gene. Although the functions of this protein have not been fully characterized, it may (1) play a role in transcriptional regulation during neuronal differentiation and pathogenesis of retinoblastoma, (2) act as a transcriptional activator of the heme-oxygenase-1 gene, and (3) be a specific effector of estrogen action. Three transcript variants encoding different isoforms have been found for this gene.[2]
# Interactions
PRDM2 has been shown to interact with Estrogen receptor alpha[3] and Retinoblastoma protein.[1] | https://www.wikidoc.org/index.php/PRDM2 | |
4d46c8f3acde837346f255df7e1f1893fef90f4d | wikidoc | PRDM9 | PRDM9
PR domain zinc finger protein 9 is a protein that in humans is encoded by the Prdm9 gene. PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain. PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.
# Domain Architecture
PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding).
# History
In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.
In 1982 a haplotype was identified controlling recombination rate wm7, which would later be identified as PRDM9.
In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3). This would later turn out to be the same PRDM9 protein independently identified later.
In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.
In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.
Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.
In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.
in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.
In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro, which was confirmed in vivo in 2016.
In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks.
# Function in Recombination
PRDM9 mediates the process of meiosis by directing the sites of homologous recombination. In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called recombination hotspots. Hotspots are regions of DNA about 1-2kb in length. There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50-100kb DNA on average. In humans, the average number of crossover recombination events per hotspot is one per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses. These hotspots are binding sites for the PRDM9 Zinc Finger array. Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and Histone 4 at lysine 36. As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.
# Notes
- ↑ positive-regulatory domain | PRDM9
PR domain[note 1] zinc finger protein 9 is a protein that in humans is encoded by the Prdm9 gene.[1] PRDM9 is responsible for positioning recombination hotspots during meiosis by binding a DNA sequence motif encoded in its zinc finger domain.[2] PRDM9 is the only speciation gene found so far in mammals, and is one of the fastest evolving genes in the genome.[3][4]
# Domain Architecture
PRDM9 has multiple domains including KRAB domain, SSXRD, PR/SET domain (H3K4 & H3K36 trimethyltransferase), and an array of C2H2 Zinc Finger domains (DNA binding).[5]
# History
In 1974 Jiri Forejt and P. Ivanyi identified a locus which they named Hst1 which controlled hybrid sterility.[6]
In 1982 a haplotype was identified controlling recombination rate wm7,[7] which would later be identified as PRDM9.[8]
In 1991 a protein binding to the minisatelite consensus sequence 5′-CCACCTGCCCACCTCT-3′ was detected and partially purified (named Msbp3 - minisatelite binding protein 3).[9] This would later turn out to be the same PRDM9 protein independently identified later.[10]
In 2005 a gene was identified (named Meisetz) that is required for progression through meiotic prophase and has H3K4 methyltransferase activity.[11]
In 2009 Jiri Forejt and colleagues identified Hst1 as Meisetz/PRDM9 - the first and so far only speciation gene in mammals.[12]
Later in 2009 PRDM9 was identified as one of the fastest evolving genes in the genome.[5][13]
In 2010 three groups independently identified PRDM9 as controlling the positioning of recombination hotspots in humans and mice.[2][14][15][16][17]
in 2012 it was shown that almost all hotspots are positioned by PRDM9 and that in its absence hotspots form near promoters.[18]
In 2014 it was reported that the PRDM9 SET domain could also trimethylate H3K36 in vitro,[19] which was confirmed in vivo in 2016.[20]
In 2016 it was shown that the hybrid sterility caused by PRDM9 can be reversed and that the sterility is caused by asymmetric double strand breaks.[21][22]
# Function in Recombination
PRDM9 mediates the process of meiosis by directing the sites of homologous recombination.[23] In humans and mice, recombination does not occur evenly throughout the genome but at particular sites along the chromosomes called recombination hotspots. Hotspots are regions of DNA about 1-2kb in length.[24] There are approximately 30,000 to 50,000 hotspots within the human genome corresponding to one for every 50-100kb DNA on average.[24] In humans, the average number of crossover recombination events per hotspot is one per 1,300 meioses, and the most extreme hotspot has a crossover frequency of one per 110 meioses.[24] These hotspots are binding sites for the PRDM9 Zinc Finger array.[25] Upon binding to DNA, PRDM9 catalyzes trimethylation of Histone 3 at lysine 4 and Histone 4 at lysine 36.[26] As a result, local nucleosomes are reorganized and through an unknown mechanism the recombination machinery is recruited to form double strand breaks.
# Notes
- ↑ positive-regulatory domain | https://www.wikidoc.org/index.php/PRDM9 | |
da0e726050c8df0a759d20822402c82e22722db2 | wikidoc | PRDX3 | PRDX3
Thioredoxin-dependent peroxide reductase, mitochondrial is an enzyme that in humans is encoded by the PRDX3 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.
# Function
This gene encodes a protein with antioxidant function and is localized in the mitochondrion. This gene shows significant nucleotide sequence similarity to the gene coding for the C22 subunit of Salmonella typhimurium alkylhydroperoxide reductase. Expression of this gene product in E. coli deficient in the C22-subunit gene rescued resistance of the bacteria to alkylhydroperoxide. The human and mouse genes are highly conserved, and they map to the regions syntenic between mouse and human chromosomes. Sequence comparisons with recently cloned mammalian homologues suggest that these genes consist of a family that is responsible for regulation of cellular proliferation, differentiation, and antioxidant functions. Two transcript variants encoding two different isoforms have been found for this gene.
# Interactions
PRDX3 has been shown to interact with MAP3K13.
# Clinical significance
It has been demonstrated that serum peroxiredoxin 3 can be a valuable biomarker for the diagnosis and assessment of hepatocellular carcinoma It has been shown that peroxiredoxin proteins protect MCF-7 breast cancer cells against doxorubicin-mediated toxicity. Additionally, it has been shown that peroxiredoxin 3 is overexpressed in prostate cancer and promotes cancer cell survival by defending cells against the damages incurred by oxidative stress. | PRDX3
Thioredoxin-dependent peroxide reductase, mitochondrial is an enzyme that in humans is encoded by the PRDX3 gene.[1][2][3] It is a member of the peroxiredoxin family of antioxidant enzymes.
# Function
This gene encodes a protein with antioxidant function and is localized in the mitochondrion. This gene shows significant nucleotide sequence similarity to the gene coding for the C22 subunit of Salmonella typhimurium alkylhydroperoxide reductase. Expression of this gene product in E. coli deficient in the C22-subunit gene rescued resistance of the bacteria to alkylhydroperoxide. The human and mouse genes are highly conserved, and they map to the regions syntenic between mouse and human chromosomes. Sequence comparisons with recently cloned mammalian homologues suggest that these genes consist of a family that is responsible for regulation of cellular proliferation, differentiation, and antioxidant functions. Two transcript variants encoding two different isoforms have been found for this gene.[3]
# Interactions
PRDX3 has been shown to interact with MAP3K13.[4]
# Clinical significance
It has been demonstrated that serum peroxiredoxin 3 can be a valuable biomarker for the diagnosis and assessment of hepatocellular carcinoma[5] It has been shown that peroxiredoxin proteins protect MCF-7 breast cancer cells against doxorubicin-mediated toxicity.[6] Additionally, it has been shown that peroxiredoxin 3 is overexpressed in prostate cancer and promotes cancer cell survival by defending cells against the damages incurred by oxidative stress.[7] | https://www.wikidoc.org/index.php/PRDX3 | |
8396dc44c4ef21cf3d555dff877f6d0644989489 | wikidoc | PRDX5 | PRDX5
Peroxiredoxin-5 (PRDX5), mitochondrial is a protein that in humans is encoded by the PRDX5 gene, located on chromosome 11.
This gene encodes a member of the six-member peroxiredoxin family of antioxidant enzymes. Like the other five members, PRDX5 is widely expressed in tissues but differs by its large subcellular distribution. In human cells, it has been shown that PRDX5 can be localized to mitochondria, peroxisomes, the cytosol, and the nucleus. Human PRDX5 is identified by virtue of the sequence homologies to yeast peroxisomal antioxidant enzyme PMP20.
Biochemically, PRDX5 is a peroxidase that can use cytosolic or mitochondrial thioredoxins to reduce alkyl hydroperoxides or peroxynitrite with high rate constants in the 106 to 107 M−1s−1 range, whereas its reaction with hydrogen peroxide is more modest, in the 105 M−1s−1 range. So far, PRDX5 has been shown to be a cytoprotective antioxidant enzyme that inhibits endogenous or exogenous peroxide accumulation.
# Structure
According to its amino acid sequence, this 2-Cys peroxiredoxin, PRDX5, is the most divergent isoform among mammalian peroxiredoxins, processing only 28% to 30% sequence identity with typical 2-Cys and 1-Cys peroxiredoxins. The divergent amino acid sequence of this atypical peroxiredoxin is reflected in its unique crystal structure. The typical peroxiredoxin is composed of a thioredoxin domain and a C-terminal, whereas PRDX5 has an N-terminal domain and a unique alpha helix replaces a loop structure in the typical thioredoxin domain. In addition, typical 2-Cys or 1-Cys peroxiredoxins are associated as anti-parallel dimers via linkage of two beta-7-strands, whereas a PRDX5 dimer is formed by close contact between an alpha-3-helix of one molecule and an alpha-5-helix from the other molecule.
# Function
As a peroxiredoxin, PRDX5 has antioxidative and cytoprotective functions during oxidative stress. Overexpression of human PRDX5 has been shown to inhibit peroxide accumulation induced by TNF-alpha, PDGF, and p53 in NIH3T3 and HeLa cells and reduce cell death by exogenous peroxide in multiple organelles of CHO, HT-22, and human tendon cells. Meanwhile, reduced expression of PRDX5 induces cell susceptibility to oxidative damage and etoposide, doxorubicin, MPP+, and peroxide-induced apoptosis. In addition, expressing human PRDX5 in other organisms or tissues such as yeast, mouse brain, and Xenopus embryos also leads to protection against oxidative stress. PRDX5 in Drosophila melanogaster has been shown to promote longevity in addition to antioxidant activity.
# Clinical significance
By examining 98 stroke patients, Kunze et al. showed an inverse correlation between stroke progression and PRDX5 concentration, suggesting that plasma PRDX5 can be a potential biomarker of inflammation in acute stroke. In human breast cancer cells, knockdown of transcription factor, GATA1, led to increased expression of PRDX5 and inhibition of apoptosis. A substantial increase in PRDX5 expression has been observed in astrocytes in multiple sclerosis lesion. PRDX5 has also been identified as a candidate risk gene for the inflammatory disease, sarcoidosis.
# Interactions
Transcription factor GATA-binding protein 1 can bind to the PRDX5 gene and lead to increased expression of PRDX5. PRDX5 has been shown to physically interact with PRDX1, PRDX2, PRDX6, SOD1, and PARK7 in at least two independent high-throughput proteomic analyses. | PRDX5
Peroxiredoxin-5 (PRDX5), mitochondrial is a protein that in humans is encoded by the PRDX5 gene, located on chromosome 11.[1]
This gene encodes a member of the six-member peroxiredoxin family of antioxidant enzymes. Like the other five members, PRDX5 is widely expressed in tissues but differs by its large subcellular distribution.[2] In human cells, it has been shown that PRDX5 can be localized to mitochondria, peroxisomes, the cytosol, and the nucleus.[3] Human PRDX5 is identified by virtue of the sequence homologies to yeast peroxisomal antioxidant enzyme PMP20.[2][4]
Biochemically, PRDX5 is a peroxidase that can use cytosolic or mitochondrial thioredoxins to reduce alkyl hydroperoxides or peroxynitrite with high rate constants in the 106 to 107 M−1s−1 range, whereas its reaction with hydrogen peroxide is more modest, in the 105 M−1s−1 range.[3] So far, PRDX5 has been shown to be a cytoprotective antioxidant enzyme that inhibits endogenous or exogenous peroxide accumulation.[3]
# Structure
According to its amino acid sequence, this 2-Cys peroxiredoxin, PRDX5, is the most divergent isoform among mammalian peroxiredoxins, processing only 28% to 30% sequence identity with typical 2-Cys and 1-Cys peroxiredoxins.[5] The divergent amino acid sequence of this atypical peroxiredoxin is reflected in its unique crystal structure. The typical peroxiredoxin is composed of a thioredoxin domain and a C-terminal, whereas PRDX5 has an N-terminal domain and a unique alpha helix replaces a loop structure in the typical thioredoxin domain.[3] In addition, typical 2-Cys or 1-Cys peroxiredoxins are associated as anti-parallel dimers via linkage of two beta-7-strands, whereas a PRDX5 dimer is formed by close contact between an alpha-3-helix of one molecule and an alpha-5-helix from the other molecule.[3]
# Function
As a peroxiredoxin, PRDX5 has antioxidative and cytoprotective functions during oxidative stress. Overexpression of human PRDX5 has been shown to inhibit peroxide accumulation induced by TNF-alpha, PDGF, and p53 in NIH3T3 and HeLa cells and reduce cell death by exogenous peroxide in multiple organelles of CHO, HT-22, and human tendon cells.[2][6][7][8][9] Meanwhile, reduced expression of PRDX5 induces cell susceptibility to oxidative damage and etoposide, doxorubicin, MPP+, and peroxide-induced apoptosis.[10][11][12][13] In addition, expressing human PRDX5 in other organisms or tissues such as yeast, mouse brain, and Xenopus embryos also leads to protection against oxidative stress.[14][15][16] PRDX5 in Drosophila melanogaster has been shown to promote longevity in addition to antioxidant activity.[17]
# Clinical significance
By examining 98 stroke patients, Kunze et al. showed an inverse correlation between stroke progression and PRDX5 concentration, suggesting that plasma PRDX5 can be a potential biomarker of inflammation in acute stroke.[18] In human breast cancer cells, knockdown of transcription factor, GATA1, led to increased expression of PRDX5 and inhibition of apoptosis.[6] A substantial increase in PRDX5 expression has been observed in astrocytes in multiple sclerosis lesion.[19] PRDX5 has also been identified as a candidate risk gene for the inflammatory disease, sarcoidosis.[20]
# Interactions
Transcription factor GATA-binding protein 1 can bind to the PRDX5 gene and lead to increased expression of PRDX5.[6] PRDX5 has been shown to physically interact with PRDX1, PRDX2, PRDX6, SOD1, and PARK7 in at least two independent high-throughput proteomic analyses.[21] | https://www.wikidoc.org/index.php/PRDX5 | |
ff0150548cfc33322002ca4de95acb7e047b4b7a | wikidoc | PRDX6 | PRDX6
Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene. It is a member of the peroxiredoxin family of antioxidant enzymes.
# Function
The protein encoded by this gene is a member of the thiol-specific antioxidant protein family. This protein is a bifunctional enzyme with two distinct active sites. It is involved in redox regulation of the cell; it can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides. It may play a role in the regulation of phospholipid turnover as well as in protection against oxidative injury.
## Model organisms
Model organisms have been used in the study of PRDX6 function. A conditional knockout mouse line, called Prdx6tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice but no significant abnormalities were observed. | PRDX6
Peroxiredoxin-6 is a protein that in humans is encoded by the PRDX6 gene.[1][2] It is a member of the peroxiredoxin family of antioxidant enzymes.
# Function
The protein encoded by this gene is a member of the thiol-specific antioxidant protein family. This protein is a bifunctional enzyme with two distinct active sites. It is involved in redox regulation of the cell; it can reduce H(2)O(2) and short chain organic, fatty acid, and phospholipid hydroperoxides. It may play a role in the regulation of phospholipid turnover as well as in protection against oxidative injury.[2]
## Model organisms
Model organisms have been used in the study of PRDX6 function. A conditional knockout mouse line, called Prdx6tm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty five tests were carried out on mutant mice but no significant abnormalities were observed.[5] | https://www.wikidoc.org/index.php/PRDX6 | |
742d31e71650e1f3202cb0c170398f619d57f68b | wikidoc | PREX1 | PREX1
Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein is a protein that in humans is encoded by the PREX1 gene.
# Function
The protein encoded by this gene acts as a guanine nucleotide exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins.
# Clinical significance
The protein has been implicated in the spread of melanoma skin cancer. | PREX1
Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein is a protein that in humans is encoded by the PREX1 gene.[1][2][3][4]
# Function
The protein encoded by this gene acts as a guanine nucleotide exchange factor for the RHO family of small GTP-binding proteins (RACs). It has been shown to bind to and activate RAC1 by exchanging bound GDP for free GTP. The encoded protein, which is found mainly in the cytoplasm, is activated by phosphatidylinositol-3,4,5-trisphosphate and the beta-gamma subunits of heterotrimeric G proteins.[4]
# Clinical significance
The protein has been implicated in the spread of melanoma skin cancer.[5] | https://www.wikidoc.org/index.php/PREX1 | |
f5caf7495db583fd96e99f1fc74fa7be48a27d27 | wikidoc | PRKCE | PRKCE
Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.
# Structure
Human PRKCE gene (Ensembl ID: ENSG00000171132) encodes the protein PKCε (Uniprot ID: Q02156), which is 737 amino acids in length with a molecular weight of 83.7 kDa. The PKC family of serine-threonine kinases contains thirteen PKC isoforms, and each isoform can be distinguished by differences in primary structure, gene expression, subcellular localization, and modes of activation. The epsilon isoform of PKC is abundantly expressed in adult cardiomyocytes, being the most highly expressed of all novel isoforms, PKC-δ, -ζ, and –η. PKCε and other PKC isoforms require phosphorylation at sites Threonine-566, Threonine-710, and Serine-729 for kinase maturation. The epsilon isoform of PKC differs from other isoforms by the position of the C2, pseudosubstrate, and C1 domains; various second messengers in different combinations can act on the C1 domain to direct subcellular translocation of PKCε.
Receptors for activated C-kinase (RACK) have been found to anchor active PKC in close proximity to substrates. PKCε appears to have preferred affinity to the RACK2 isoform; specifically, the C2 domain of PKCε at amino acids 14–21 (also known as εV1-2) binds RACK2, and peptide inhibitors targeting εV1-2 inhibit PKCε translocation and function in cardiomyocytes, while peptide agonists augment translocation. It has been demonstrated that altering the dynamics of the RACK2 and RACK1 interaction with PKCε can influence cardiac muscle phenotypes.
Activated PKCε translocates to various intracellular targets. In cardiac muscle, PKCε translocates to sarcomeres at Z-lines following α-adrenergic and endothelin (ET)A-receptor stimulation. A myriad of agonists have also been shown to induce the translocation of PKCε from the cytosolic to particulate fraction in cardiomyocytes, including but not limited to PMA or norepinephrine;arachidonic acid;ET-1 and phenylephrine; angiotensin II and diastolic stretch; adenosine; hypoxia and Akt-induced stem cell factor; ROS generated via pharmacologic activation of the mitochondrial potassium-sensitive ATP channel (mitoK(ATP)) and the endogenous G-protein coupled receptor ligand, apelin.
# Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been shown to be involved in many different cellular functions, such as apoptosis, cardioprotection from ischemia, heat shock response, as well as insulin exocytosis.
## Cardiac muscle sarcomeric contractile function
PKCε translocates to cardiac muscle sarcomeres and modulates contractility of the myocardium. PKCε binds RACK2 at Z-lines with an EC50 of 86 nM; PKCε also binds at costameres to syndecan-4. PKCε has been shown to bind F-actin in neurons, which modulates synaptic function and differentiation; however it is unknown whether PKCε binds sarcomeric actin in muscle cells. Sarcomeric proteins have been identified in PKCε signaling complexes, including actin, cTnT, tropomyosin, desmin, and myosin light chain-2; in mice expressing a constitutively-active PKCε, all sarcomeric proteins showed greater association with PKCε, and the cTnT, tropomyosin, desmin and myosin light chain-2 exhibited changes in post-translational modifications.
PKCε binds and phosphorylates cardiac troponin I (cTnI) and cardiac troponin T (cTnT) in complex with troponin C (cTnC); phosphorylation on cTnI at residues Serine-43, Serine-45, and Threonine-144 cause depression of actomyosin S1 MgATPase function. These studies were further supported by those performed in isolated, skinned cardiac muscle fibers, showing that in vitro phosphorylation of cTnI by PKCε or Serine-43/45 mutation to Glutamate to mimic phosphorylation desensitized myofilaments to calcium and decreased maximal tension and filament sliding speed. Phosphorylation on cTnI at Serine-5/6 also showed this depressive effect. Further support was gained from in vivo studies in which mice expressing a mutant cTnI (Serine43/45Alanine) exhibited enhanced cardiac contractility.
## Cardiac muscle mitochondrial metabolism and function
In addition to sarcomeres, PKCε also targets cardiac mitochondria. Proteomic analysis of PKCε signaling complexes in mice expressing a constitutively-active, overexpressed PKCε identified several interacting partners at mitochondria whose protein abundance and posttranslational modifications were altered in the transgenic mice. This study was the first to demonstrate PKCε at the inner mitochondrial membrane, and it was found that PKCε binds several mitochondrial proteins involved in glycolysis, TCA cycle, beta oxidation, and ion transport. However, it remained unclear how PKCε translocates from the outer to inner mitochondrial membrane until Budas et al. discovered that heat shock protein 90 (Hsp90) coordinates with the translocase of the outer mitochondrial membrane-20 (Tom20) to translocate PKCε following a preconditioning stimulus. Specifically, a seven amino acid peptide, termed TAT-εHSP90, homologous to the Hsp90 sequence within the PKCε C2 domain induced translocation of PKCε to the inner mitochondrial membrane and cardioprotection.
PKCε has also been shown to play a role in modulating mitochondrial permeability transition (MPT); the addition of PKCε to cardiomyocytes inhibits MPT, though the mechanism is unclear. Initially, PKCε was thought to protect mitochondria from MPT through its association with VDAC1, ANT, and hexokinase II; however, genetic studies have since ruled this out and subsequent studies have identified the F0/F1 ATP synthase as a core inner mitochondrial membrane component and Bax and Bak as potential outer membrane components These findings have opened up new avenues of investigation for the role of PKCε at mitochondria. Several likely targets of PKCε action affecting MPT have been discovered. PKCε interacts with ERK, JNKs and p38, and PKCε directly or indirectly phosphorylates ERK and subsequently Bad. PKCε also interacts with Bax in cancer cells, and PKCε modulates its dimerization and function. Activation of PKCε with the specific activator, εRACK, prior to ischemic injury has shown to be associated with phosphorylation of the F0/F1 ATP synthase. Moreover, the modulatory component, ANT is regulated by PKCε. These data suggest that PKCε may act at multiple modulatory targets of MPT function; further studies are required to unveil the specific mechanism.
# Clinical significance
## Cardiac hypertrophy and heart failure
Findings of PKCε phosphorylation in animal models have been verified in humans; PKCε phosphorylates cTnI, cTnT, and MyBPC and depresses the sensitivity of myofilaments to calcium. PKCε induction occurs in the development of cardiac hypertrophy, following stimuli such as myotrophin, mechanical stretch and hypertension. The precise role of PKCε in hypertrophic induction has been debated. The inhibition of PKCε during transition from hypertrophy to heart failure enhances longevity; however, inhibition of PKCε translocation via a peptide inhibitor increases cardiomyocyte size and expression of hypertrophic gene panel. A role for focal adhesion kinase at costameres in strain-sensing and modulation of sarcomere length has been linked to hypertrophy. The activation of FAK by PKCε occurs following a hypertrophic stimulus, which modulates sarcomere assembly. PKCε also regulates CapZ dynamics following cyclic strain.
Transgenic studies involving PKCε have also shed light on its function in vivo. Cardiac-specific overexpression of constitutively-active PKCε (9-fold increase in PKCε protein, 4-fold increase in activity) induced cardiac hypertrophy characterizes by enhanced anterior and posterior left ventricular wall thickness. A later study unveiled that the aging of PKCε transgenic mice brought on dilated cardiomyopathy and heart failure by 12 months of age,] characterized by a preserved Frank-Starling mechanism and exhausted contractile reserve. Crossing PKCε transgenic mice with mutant cTnI mice lacking PKCε phosphorylation sites (Serine-43/Serine-45 mutated to Alanine) attenuated the contractile dysfunction and hypertrophic marker expression, offering critical mechanistic insights.
## Cardioprotection against Ischemic injury
JM Downey was the first to introduce the role of PKC in cardioprotection against ischemia-reperfusion injury in 1994,; this seminal idea stimulated a series of studies which examined the different isoforms of PKC. PKCε has been demonstrated to be a central player in preconditioning in multiple independent studies, with its best known actions at cardiac mitochondria. It was first demonstrated by Ping et al. that in five distinct preconditioning regimens in conscious rabbits, the epsilon isoform of PKC specifically translocated from the cytosolic to particulate fraction. This finding was validated by multiple independent studies occurring shortly thereafter, and has since been observed in multiple animal models and human tissue, as well as in studies employing transgenesis and PKCε activators/inhibitors.
Mitochondrial targets of PKCε involved in cardioprotection have been actively pursued, since the translocation of PKCε to mitochondria following protective stimuli is one of the most well-accepted cardioprotective paradigms. PKCε has been shown to target and phosphorylate alcohol dehydrogenase 2 (ALDH2) following preconditioning stimuli, which increased the activity of ALDH2 and reduced infarct size. Moreover, PKCε interacts with cytochrome c oxidase subunit IV (COIV), and preconditioning stimuli evoked phosphorylation of COIV and stabilization of COIV protein and activity. The mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) also interacts with PKCε; phosphorylation of mitoK(ATP) following preconditioning stimuli potentiates channel opening. PKCε modulates the interaction between subunit Kir6.1 of mitoK(ATP) and connexin-43, whose interaction confers cardioprotection. Lastly, several mitochondrial metabolic targets of PKCε phosphorylation involved in cardioprotection following activation with εRACK have been identified, including mitochondrial respiratory complexes I, II and III, as well as proteins involved in glycolysis, lipid oxidation, ketone body metabolism and heat shock proteins.
The role of PKCε acting in non-mitochondrial regions of cardiomyocytes is less well understood, though some studies have identified sarcomeric targets. PKCε translocation to sarcomeres and phosphorylation of cTnI and cMyBPC is involved in the κ-opioid- and α-adrenergic-dependent preconditioning that slows myosin cycling rate, thus protecting the contractile apparatus from damage. Activation of PKCε by εRACK prior to ischemia was also found to phosphorylate Ventricular myosin light chain-2, however the functional significance remains elusive. Actin-capping protein, CapZ appears to affect the localization of PKCε to Z-lines and modulates the cardiomyocyte response to ischemic injury. Cardioprotection in mice with reduction of CapZ showed enhancement in PKCε translocation to sarcomeres, thus suggesting that CapZ may compete with PKCε for the binding of RACK2.
## Other functions
Knockout and molecular studies in mice suggest that this kinase is important for regulating behavioural response to morphine and alcohol. It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.
# Substrates and interactions
PKC-epsilon has a wide variety of substrates, including ion channels, other signalling molecules and cytoskeletal proteins.
PKC-epsilon has been shown to interact with:
- ACTA1,
- COPB2,
- CFTR,
- KRT1,
- GNB2L1,
- MYH9,
- VDAC1, and
- YWHAZ. | PRKCE
Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene.[1][2] PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.
# Structure
Human PRKCE gene (Ensembl ID: ENSG00000171132) encodes the protein PKCε (Uniprot ID: Q02156), which is 737 amino acids in length with a molecular weight of 83.7 kDa. The PKC family of serine-threonine kinases contains thirteen PKC isoforms, and each isoform can be distinguished by differences in primary structure, gene expression, subcellular localization, and modes of activation.[3] The epsilon isoform of PKC is abundantly expressed in adult cardiomyocytes,[4][5][6][7] being the most highly expressed of all novel isoforms, PKC-δ, -ζ, and –η.[8] PKCε and other PKC isoforms require phosphorylation at sites Threonine-566, Threonine-710, and Serine-729 for kinase maturation.[9] The epsilon isoform of PKC differs from other isoforms by the position of the C2, pseudosubstrate, and C1 domains; various second messengers in different combinations can act on the C1 domain to direct subcellular translocation of PKCε.[5][10]
Receptors for activated C-kinase (RACK) have been found to anchor active PKC in close proximity to substrates.[11] PKCε appears to have preferred affinity to the RACK2 isoform; specifically, the C2 domain of PKCε at amino acids 14–21 (also known as εV1-2) binds RACK2, and peptide inhibitors targeting εV1-2 inhibit PKCε translocation and function in cardiomyocytes,[12] while peptide agonists augment translocation.[13] It has been demonstrated that altering the dynamics of the RACK2 and RACK1 interaction with PKCε can influence cardiac muscle phenotypes.[14]
Activated PKCε translocates to various intracellular targets.[9][15] In cardiac muscle, PKCε translocates to sarcomeres at Z-lines following α-adrenergic and endothelin (ET)A-receptor stimulation.[5][16] A myriad of agonists have also been shown to induce the translocation of PKCε from the cytosolic to particulate fraction in cardiomyocytes, including but not limited to PMA or norepinephrine;[5]arachidonic acid;[17]ET-1 and phenylephrine;[18][19] angiotensin II and diastolic stretch;[20] adenosine;[21] hypoxia and Akt-induced stem cell factor;[22] ROS generated via pharmacologic activation of the mitochondrial potassium-sensitive ATP channel (mitoK(ATP))[23] and the endogenous G-protein coupled receptor ligand, apelin.[24]
# Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This kinase has been shown to be involved in many different cellular functions, such as apoptosis, cardioprotection from ischemia, heat shock response, as well as insulin exocytosis.
## Cardiac muscle sarcomeric contractile function
PKCε translocates to cardiac muscle sarcomeres and modulates contractility of the myocardium. PKCε binds RACK2 at Z-lines with an EC50 of 86 nM;[25] PKCε also binds at costameres to syndecan-4.[26] PKCε has been shown to bind F-actin in neurons, which modulates synaptic function and differentiation;[27][28] however it is unknown whether PKCε binds sarcomeric actin in muscle cells. Sarcomeric proteins have been identified in PKCε signaling complexes, including actin, cTnT, tropomyosin, desmin, and myosin light chain-2; in mice expressing a constitutively-active PKCε, all sarcomeric proteins showed greater association with PKCε, and the cTnT, tropomyosin, desmin and myosin light chain-2 exhibited changes in post-translational modifications.[29]
PKCε binds and phosphorylates cardiac troponin I (cTnI) and cardiac troponin T (cTnT) in complex with troponin C (cTnC);[30] phosphorylation on cTnI at residues Serine-43, Serine-45, and Threonine-144 cause depression of actomyosin S1 MgATPase function.[31][32] These studies were further supported by those performed in isolated, skinned cardiac muscle fibers, showing that in vitro phosphorylation of cTnI by PKCε or Serine-43/45 mutation to Glutamate to mimic phosphorylation desensitized myofilaments to calcium and decreased maximal tension and filament sliding speed.[33] Phosphorylation on cTnI at Serine-5/6 also showed this depressive effect.[34] Further support was gained from in vivo studies in which mice expressing a mutant cTnI (Serine43/45Alanine) exhibited enhanced cardiac contractility.[35]
## Cardiac muscle mitochondrial metabolism and function
In addition to sarcomeres, PKCε also targets cardiac mitochondria.[29][36] Proteomic analysis of PKCε signaling complexes in mice expressing a constitutively-active, overexpressed PKCε identified several interacting partners at mitochondria whose protein abundance and posttranslational modifications were altered in the transgenic mice.[29] This study was the first to demonstrate PKCε at the inner mitochondrial membrane,[29] and it was found that PKCε binds several mitochondrial proteins involved in glycolysis, TCA cycle, beta oxidation, and ion transport.[37] However, it remained unclear how PKCε translocates from the outer to inner mitochondrial membrane until Budas et al. discovered that heat shock protein 90 (Hsp90) coordinates with the translocase of the outer mitochondrial membrane-20 (Tom20) to translocate PKCε following a preconditioning stimulus.[38][39] Specifically, a seven amino acid peptide, termed TAT-εHSP90, homologous to the Hsp90 sequence within the PKCε C2 domain induced translocation of PKCε to the inner mitochondrial membrane and cardioprotection.[40]
PKCε has also been shown to play a role in modulating mitochondrial permeability transition (MPT); the addition of PKCε to cardiomyocytes inhibits MPT,[36] though the mechanism is unclear. Initially, PKCε was thought to protect mitochondria from MPT through its association with VDAC1, ANT, and hexokinase II;[36] however, genetic studies have since ruled this out[41][42] and subsequent studies have identified the F0/F1 ATP synthase as a core inner mitochondrial membrane component[43][44][45][46] and Bax and Bak as potential outer membrane components[47] These findings have opened up new avenues of investigation for the role of PKCε at mitochondria. Several likely targets of PKCε action affecting MPT have been discovered. PKCε interacts with ERK, JNKs and p38, and PKCε directly or indirectly phosphorylates ERK and subsequently Bad.[48] PKCε also interacts with Bax in cancer cells, and PKCε modulates its dimerization and function.[49][50] Activation of PKCε with the specific activator, εRACK, prior to ischemic injury has shown to be associated with phosphorylation of the F0/F1 ATP synthase.[51] Moreover, the modulatory component, ANT is regulated by PKCε.[36] These data suggest that PKCε may act at multiple modulatory targets of MPT function; further studies are required to unveil the specific mechanism.
# Clinical significance
## Cardiac hypertrophy and heart failure
Findings of PKCε phosphorylation in animal models have been verified in humans; PKCε phosphorylates cTnI, cTnT, and MyBPC and depresses the sensitivity of myofilaments to calcium.[52] PKCε induction occurs in the development of cardiac hypertrophy, following stimuli such as myotrophin,[53] mechanical stretch and hypertension.[54] The precise role of PKCε in hypertrophic induction has been debated. The inhibition of PKCε during transition from hypertrophy to heart failure enhances longevity;[55] however, inhibition of PKCε translocation via a peptide inhibitor increases cardiomyocyte size and expression of hypertrophic gene panel.[56] A role for focal adhesion kinase at costameres in strain-sensing and modulation of sarcomere length has been linked to hypertrophy. The activation of FAK by PKCε occurs following a hypertrophic stimulus, which modulates sarcomere assembly.[57][58] PKCε also regulates CapZ dynamics following cyclic strain.[59]
Transgenic studies involving PKCε have also shed light on its function in vivo. Cardiac-specific overexpression of constitutively-active PKCε (9-fold increase in PKCε protein, 4-fold increase in activity) induced cardiac hypertrophy characterizes by enhanced anterior and posterior left ventricular wall thickness.[60] A later study unveiled that the aging of PKCε transgenic mice brought on dilated cardiomyopathy and heart failure by 12 months of age,[61]] characterized by a preserved Frank-Starling mechanism and exhausted contractile reserve.[62] Crossing PKCε transgenic mice with mutant cTnI mice lacking PKCε phosphorylation sites (Serine-43/Serine-45 mutated to Alanine) attenuated the contractile dysfunction and hypertrophic marker expression, offering critical mechanistic insights.[63]
## Cardioprotection against Ischemic injury
JM Downey was the first to introduce the role of PKC in cardioprotection against ischemia-reperfusion injury in 1994,;[64] this seminal idea stimulated a series of studies which examined the different isoforms of PKC. PKCε has been demonstrated to be a central player in preconditioning in multiple independent studies, with its best known actions at cardiac mitochondria. It was first demonstrated by Ping et al. that in five distinct preconditioning regimens in conscious rabbits, the epsilon isoform of PKC specifically translocated from the cytosolic to particulate fraction.[8][65] This finding was validated by multiple independent studies occurring shortly thereafter,[66][67] and has since been observed in multiple animal models[68][69][70] and human tissue,[71] as well as in studies employing transgenesis and PKCε activators/inhibitors.[72]
Mitochondrial targets of PKCε involved in cardioprotection have been actively pursued, since the translocation of PKCε to mitochondria following protective stimuli is one of the most well-accepted cardioprotective paradigms. PKCε has been shown to target and phosphorylate alcohol dehydrogenase 2 (ALDH2) following preconditioning stimuli, which increased the activity of ALDH2 and reduced infarct size.[73][74] Moreover, PKCε interacts with cytochrome c oxidase subunit IV (COIV), and preconditioning stimuli evoked phosphorylation of COIV and stabilization of COIV protein and activity.[75] The mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) also interacts with PKCε; phosphorylation of mitoK(ATP) following preconditioning stimuli potentiates channel opening.[76][77] PKCε modulates the interaction between subunit Kir6.1 of mitoK(ATP) and connexin-43, whose interaction confers cardioprotection.[78] Lastly, several mitochondrial metabolic targets of PKCε phosphorylation involved in cardioprotection following activation with εRACK have been identified, including mitochondrial respiratory complexes I, II and III, as well as proteins involved in glycolysis, lipid oxidation, ketone body metabolism and heat shock proteins.[79]
The role of PKCε acting in non-mitochondrial regions of cardiomyocytes is less well understood, though some studies have identified sarcomeric targets. PKCε translocation to sarcomeres and phosphorylation of cTnI and cMyBPC is involved in the κ-opioid- and α-adrenergic-dependent preconditioning that slows myosin cycling rate, thus protecting the contractile apparatus from damage.[80][81] Activation of PKCε by εRACK prior to ischemia was also found to phosphorylate Ventricular myosin light chain-2,[82] however the functional significance remains elusive. Actin-capping protein, CapZ appears to affect the localization of PKCε to Z-lines[83] and modulates the cardiomyocyte response to ischemic injury. Cardioprotection in mice with reduction of CapZ showed enhancement in PKCε translocation to sarcomeres,[84] thus suggesting that CapZ may compete with PKCε for the binding of RACK2.
## Other functions
Knockout and molecular studies in mice suggest that this kinase is important for regulating behavioural response to morphine[85] and alcohol.[86][87] It also plays a role lipopolysaccharide (LPS)-mediated signaling in activated macrophages and in controlling anxiety-like behavior.[88]
# Substrates and interactions
PKC-epsilon has a wide variety of substrates, including ion channels, other signalling molecules and cytoskeletal proteins.[89]
PKC-epsilon has been shown to interact with:
- ACTA1,[90]
- COPB2,[90]
- CFTR,[91]
- KRT1,[90]
- GNB2L1,[91]
- MYH9,[90]
- VDAC1,[36] and
- YWHAZ.[92] | https://www.wikidoc.org/index.php/PRKCE | |
c1405c81be575e0a43151ac4749c40a7c93a5dd9 | wikidoc | PRKCQ | PRKCQ
Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.
# Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipid-dependent protein kinase. This kinase is important for T-cell activation. It is required for the activation of the transcription factors NF-kappaB and AP-1, and may link the T cell receptor (TCR) signaling complex to the activation of the transcription factors. PKC-θ also play a role in the apoptosis of lymphoid cells where it negatively influence and delay the aggregation of spectrin in an early phase of apoptosis.
## The role of PKC-θ in T cells
PKC-θ has a role in the transduction of signals in T cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from TCR and CD28 receptors. A junction between an APC (an antigen presenting cell) and a T cell through their TCR and MHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of T cells between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing LFA-1 and ICAM-1). In regulatory T cells, PKC-θ is depleted depleted from the region of immunological synapse, whereas in effector T cells, PKC θ is present. As a result of costimulation by CD28 and TCR, PKC-θ is sumoylated by SUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse. Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor AP-1 (activating protein-1). PKC-θ also initiates the assembly of proteins Carma-1, Bcl-10 and Malt-1 by phosphorylation of Carma-1. This complex of three proteins activates the transcription factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells). Thus, PKC-θ promotes inflammation in effector T cells. PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells. The kinase PKC-θ is crucial for function of Th2 and Th17. Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histons increases the accessibility of transcriptional-memory-responsive genes in memory T cells. PKC-θ plays a role in anti-tumor activity of NK cells. It was observed that in mice without PKC-θ, MHCI-deficient tumors are more often.
## The possible application of its inhibitors
Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or by Th2 (causing allergies) without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and cause lower production of IL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases. PKC-θ could be a target of inhibitors in the therapy of allergies.
The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity (catalytic sites among PKCs are very similar). Allosteric inhibitors have to be more specif to concrete isoforms of PKC.s.
# Interactions
PRKCQ has been shown to interact with:
- AKT1
- FYN,
- GLRX3, and
- VAV1.
PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.
# Inhibitors
- (R)-2-((S)-4-(3-Chloro-5-fluoro-6-(1H-pyrazolopyridin- 3-yl)pyridin-2-yl)piperazin-2-yl)-3-methylbutan-2-ol | PRKCQ
Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene.[1] PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells[1] with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.[2]
# Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipid-dependent protein kinase. This kinase is important for T-cell activation. It is required for the activation of the transcription factors NF-kappaB and AP-1, and may link the T cell receptor (TCR) signaling complex to the activation of the transcription factors.[3] PKC-θ also play a role in the apoptosis of lymphoid cells where it negatively influence and delay the aggregation of spectrin in an early phase of apoptosis.[4]
## The role of PKC-θ in T cells
PKC-θ has a role in the transduction of signals in T cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from TCR and CD28 receptors. A junction between an APC (an antigen presenting cell) and a T cell through their TCR and MHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of T cells between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing LFA-1 and ICAM-1). In regulatory T cells, PKC-θ is depleted depleted from the region of immunological synapse, whereas in effector T cells, PKC θ is present.[2] As a result of costimulation by CD28 and TCR, PKC-θ is sumoylated by SUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse.[5] Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor AP-1 (activating protein-1). PKC-θ also initiates the assembly of proteins Carma-1, Bcl-10 and Malt-1 by phosphorylation of Carma-1. This complex of three proteins activates the transcription factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells).[6] Thus, PKC-θ promotes inflammation in effector T cells.[2] PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.[7] The kinase PKC-θ is crucial for function of Th2 and Th17.[2] Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histons increases the accessibility of transcriptional-memory-responsive genes in memory T cells.[8] PKC-θ plays a role in anti-tumor activity of NK cells. It was observed that in mice without PKC-θ, MHCI-deficient tumors are more often.[9]
## The possible application of its inhibitors
Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or by Th2 (causing allergies)[7] without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and cause lower production of IL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases.[2] PKC-θ could be a target of inhibitors in the therapy of allergies.[10]
The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity (catalytic sites among PKCs are very similar). Allosteric inhibitors have to be more specif to concrete isoforms of PKC.[2]s.
# Interactions
PRKCQ has been shown to interact with:
- AKT1[11]
- FYN,[12]
- GLRX3,[13] and
- VAV1.[14]
PRKCQ has been shown to phosphorylate CARD11 as part of the NF-κB signaling pathway.[15]
# Inhibitors
- (R)-2-((S)-4-(3-Chloro-5-fluoro-6-(1H-pyrazolo[3,4-b]pyridin- 3-yl)pyridin-2-yl)piperazin-2-yl)-3-methylbutan-2-ol[16] | https://www.wikidoc.org/index.php/PRKCQ | |
7d28e9a6cee04706f02414268bd79ba50ddbfc05 | wikidoc | PRMT1 | PRMT1
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene.
# Function
The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
# Model organisms
Model organisms have been used in the study of PRMT1 function. A conditional knockout mouse line, called Prmt1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and females displayed increased circulating creatinine levels.
# Interactions
PRMT1 has been shown to interact with:
- BTG1,
- BTG2,
- DHX9,
- FUS,
- HNRNPR,
- HNRPK,
- IFNAR1,
- ILF3,
- KHDRBS1, and
- SUPT5H. | PRMT1
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene.[1]
# Function
The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.[2]
# Model organisms
Model organisms have been used in the study of PRMT1 function. A conditional knockout mouse line, called Prmt1tm1a(EUCOMM)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty three tests were carried out on mutant mice and three significant abnormalities were observed.[4] No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and females displayed increased circulating creatinine levels.[4]
# Interactions
PRMT1 has been shown to interact with:
- BTG1,[12][13]
- BTG2,[12][13]
- DHX9,[14]
- FUS,[15][16][17]
- HNRNPR,[16][17]
- HNRPK,[16][18]
- IFNAR1,[19]
- ILF3,[15][20]
- KHDRBS1,[18] and
- SUPT5H.[21] | https://www.wikidoc.org/index.php/PRMT1 | |
db8d3a925b44204defc83a60619b13afdca7096d | wikidoc | PRMT3 | PRMT3
Protein arginine N-methyltransferase 3 is an enzyme that in humans is encoded by the PRMT3 gene.
# Model organisms
Model organisms have been used in the study of PRMT3 function. A conditional knockout mouse line, called Prmt3tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty seven tests were carried out on mutant mice and seven significant abnormalities were observed. Fewer than predicted homozygous mutant mice survived until weaning due to hydrocephaly. The remaining tests were carried out on both heterozygous and homozygous mutant adult mice. Male heterzygous mice had a decreased respiratory quotient. Homozygous females had decreased body weight, length and bone mineral density. Homozygous males had abnormal peripheral blood lymphocyte counts and homozygotes of both sex had eye abnormalities.
# Interactions
PRMT3 has been shown to interact with RPS2. | PRMT3
Protein arginine N-methyltransferase 3 is an enzyme that in humans is encoded by the PRMT3 gene.[1][2]
# Model organisms
Model organisms have been used in the study of PRMT3 function. A conditional knockout mouse line, called Prmt3tm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty seven tests were carried out on mutant mice and seven significant abnormalities were observed.[9] Fewer than predicted homozygous mutant mice survived until weaning due to hydrocephaly. The remaining tests were carried out on both heterozygous and homozygous mutant adult mice. Male heterzygous mice had a decreased respiratory quotient. Homozygous females had decreased body weight, length and bone mineral density. Homozygous males had abnormal peripheral blood lymphocyte counts and homozygotes of both sex had eye abnormalities.[9]
# Interactions
PRMT3 has been shown to interact with RPS2.[17] | https://www.wikidoc.org/index.php/PRMT3 | |
d05b8edcdc94a453833da723b44c0c5bb4b486ea | wikidoc | PROX1 | PROX1
Prospero homeobox protein 1 is a protein that in humans is encoded by the PROX1 gene.
# Interactions
PROX1 has been shown to interact with EP300.
# Production
PROX1 is produced primarily in the dentate gyrus in the mouse, and in the dentate gyrus and white matter in humans. Gene expression data for mouse, human and macaque from the Allen Brain Atlases can be found here.
# Clinical significance
PROX1 is used as a marker for lymphatic endothelium in biopsy samples. | PROX1
Prospero homeobox protein 1 is a protein that in humans is encoded by the PROX1 gene.[1][2]
# Interactions
PROX1 has been shown to interact with EP300.[3]
# Production
PROX1 is produced primarily in the dentate gyrus in the mouse, and in the dentate gyrus and white matter in humans. Gene expression data for mouse, human and macaque from the Allen Brain Atlases can be found here.
# Clinical significance
PROX1 is used as a marker for lymphatic endothelium in biopsy samples. | https://www.wikidoc.org/index.php/PROX1 | |
0b080f239da34873ecd53810f60392b41966cb7a | wikidoc | PRPF6 | PRPF6
Pre-mRNA-processing factor 6 is a protein that in humans is encoded by the PRPF6 gene.
The protein encoded by this gene appears to be involved in pre-mRNA splicing, possibly acting as a bridging factor between U5 and U4/U6 snRNPs in formation of the spliceosome. The encoded protein also can bind androgen receptor, providing a link between transcriptional activation and splicing.
# Interactions
PRPF6 has been shown to interact with TXNL4B, ARAF and Androgen receptor. | PRPF6
Pre-mRNA-processing factor 6 is a protein that in humans is encoded by the PRPF6 gene.[1][2][3]
The protein encoded by this gene appears to be involved in pre-mRNA splicing, possibly acting as a bridging factor between U5 and U4/U6 snRNPs in formation of the spliceosome. The encoded protein also can bind androgen receptor, providing a link between transcriptional activation and splicing.[3]
# Interactions
PRPF6 has been shown to interact with TXNL4B,[4] ARAF[5][6] and Androgen receptor.[7] | https://www.wikidoc.org/index.php/PRPF6 | |
cb14ad7c0524ff7dc748a7c1ce57f3d521328045 | wikidoc | PRR29 | PRR29
PRR29 is a protein located on human chromosome 17 that in humans is encoded by the PRR29 gene.
It is also commonly known as C17orf72. The gene has a size of 5961 base pairs and contains five exons.
# Gene
PRR29 is located on the long arm of chromosome 17 (17q23.3), starting at 63998344 and ending at 64004305. The gene spans 5961 base pairs and is oriented on the plus strand. Genes SNHG25 and LOC105371858 neighbor PRR29 on chromosome 17.The gene ICAM2 is located on the negative strand, directly opposite of PRR29.
# mRNA
The gene has 12 common splice variants and one unspliced form. The longest transcribed mRNA is made up of 3048 base pairs and the transcribed protein sequence for this mRNA is 189 amino acids.
# Protein
## General properties
Homo sapiens PRR29 has several protein isoforms, with the longest being 236 amino acids. PRR29 has a predicted Isoelectric point of 5.23 and a predicted Molecular weight of 26.1 kilodaltons. PRR29 is characterized by a larger than average proportion of prolines (19.1%) and a smaller than average amount of asparagines (0.4%)
## Domains
PRR29 contains a proline rich region within its sequence from amino acids 73 to 166. A domain of unknown function, DUF 4587, is also present from amino acids 39 to 113. DUF 4587 is usually between 64 and 79 amino acids long and contains the two sequence motifs QNAQ and HHH. PRR29 is predicted to contain multiple alpha helix and beta-sheet forming regions. Specifically, the DUF 4587 region is predicted to form an alpha helix.
## Subcellular localization
Using PSORTII, PRR29 is predicted to localize in the nucleus of the cell. PSORTII does not predict any targeting sequences or signal peptides.
## Modification
PRR29 is predicted to undergo sumoylation, acetylation, and serine, threonine and tyrosine phosphorylation.
## Interactions
The interactome of PRR29 is not yet well characterized. One experimental study found that a Sus scrofa PRR29-like protein interacts with the N-terminal protease of classical swine fever virus (CSFV).
# Expression
PRR29 is ubiquitously expressed throughout the body. However, there is particularly high expression in the ovaries, muscle, heart, testes, and thymus. According to PaxDb, PRR29 abundance falls in the bottom 5% relative to other proteins.
# Homology
PRR29 has a single known paralog, C21orf58. PRR29 is well conserved among chordates and PRR29-like proteins containing the DUF 4587 have been predicted in protostomes, such as Mollusca and Annelida. DUF 4587 is highly conserved in all PRR29 orthologs and is also present in its paralog, C21orf58. This domain has been found in species as distantly related as Capitella teleta, which diverged from humans 847 million years ago. | PRR29
PRR29 is a protein located on human chromosome 17 that in humans is encoded by the PRR29 gene.[1][2]
It is also commonly known as C17orf72. The gene has a size of 5961 base pairs and contains five exons.[1]
# Gene
PRR29 is located on the long arm of chromosome 17 (17q23.3), starting at 63998344 and ending at 64004305.[1] The gene spans 5961 base pairs and is oriented on the plus strand. Genes SNHG25 and LOC105371858 neighbor PRR29 on chromosome 17.The gene ICAM2 is located on the negative strand, directly opposite of PRR29.
# mRNA
The gene has 12 common splice variants and one unspliced form.[3] The longest transcribed mRNA is made up of 3048 base pairs and the transcribed protein sequence for this mRNA is 189 amino acids.[1]
# Protein
## General properties
Homo sapiens PRR29 has several protein isoforms, with the longest being 236 amino acids.[1] PRR29 has a predicted Isoelectric point of 5.23 and a predicted Molecular weight of 26.1 kilodaltons. PRR29 is characterized by a larger than average proportion of prolines (19.1%) and a smaller than average amount of asparagines (0.4%)[5]
## Domains
PRR29 contains a proline rich region within its sequence from amino acids 73 to 166. A domain of unknown function, DUF 4587, is also present from amino acids 39 to 113.[6] DUF 4587 is usually between 64 and 79 amino acids long and contains the two sequence motifs QNAQ and HHH. PRR29 is predicted to contain multiple alpha helix and beta-sheet forming regions. Specifically, the DUF 4587 region is predicted to form an alpha helix.[7]
## Subcellular localization
Using PSORTII, PRR29 is predicted to localize in the nucleus of the cell.[8] PSORTII does not predict any targeting sequences or signal peptides.
## Modification
PRR29 is predicted to undergo sumoylation, acetylation, and serine, threonine and tyrosine phosphorylation.[9]
## Interactions
The interactome of PRR29 is not yet well characterized. One experimental study found that a Sus scrofa PRR29-like protein interacts with the N-terminal protease of classical swine fever virus (CSFV).[10]
# Expression
PRR29 is ubiquitously expressed throughout the body. However, there is particularly high expression in the ovaries, muscle, heart, testes, and thymus.[12] According to PaxDb, PRR29 abundance falls in the bottom 5% relative to other proteins.[13]
# Homology
PRR29 has a single known paralog, C21orf58.[14] PRR29 is well conserved among chordates and PRR29-like proteins containing the DUF 4587 have been predicted in protostomes, such as Mollusca and Annelida.[15] DUF 4587 is highly conserved in all PRR29 orthologs and is also present in its paralog, C21orf58.[16] This domain has been found in species as distantly related as Capitella teleta, which diverged from humans 847 million years ago.[17] | https://www.wikidoc.org/index.php/PRR29 | |
e59f3db4a37847d61f11ea550d8c0b2d29035c7b | wikidoc | PRR32 | PRR32
PRR32 is a protein that in humans is encoded by the CXorf64 (Chromosome X Open Reading Frame 64) gene. It was also found that the homologs of the PRR32 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, and rat. It was also found through ncbi that 82 organisms have orthologs with human gene PRR323.
PRR32 (CXorf64) seems to be involved with a group of genes over-expressed in ALS (Amyotrophic lateral sclerosis), evident from a study aiming to study gene expression patterns in muscles from patients with amyotrophic lateral sclerosis and multifocal motor neuropathy.
# Gene
The gene is located on Chromosome X, at position Xq25, and is 2023 bases long (significantly small when compared to other genes). Its location is at the antisense (+) strand. As shown in the graphic below, it is flanked by upstream by the DKAF12l1 shown in green on the left and downstream by LOC10. CXorf64 is the blue column shown in the middle.
## Transcript
CXorf64 has 1 exon which ultimately forms 1 transcript variant. This gene is expressed most in muscle tissue. There are no known isoforms in which CXorf64 is expressed.
# Protein
## General Properties
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is marked by long alpha-helices localized to the end of the protein opposite the N- and C- terminal ends
## Expression
According to microarray-assessed tissue expression analysis by NCBI GEO, the gene CXorf64 has average expression levels in most tissues save for, prostate, and heart, fat, and endometrium which have relatively low levels of expression (~25th percentile of tissue gene expression) . Almost every microarray study determined very low levels of gene expression across all tissues assessed . This evidence prompted further analysis with other tools. While no tissue analysis was present on Allen Brain Atlas or genepaint, the Human Protein Atlas suggested that the gene was more highly expressed in heart, prostate, and a and fat tissues .
## Sub-cellular Location
It synthesizes in the cell cytoplasm and is predicted to localize in the mitochondria. It is predicted to localize in the nucleus, plasma membrane, extracellular, mitochondrion, peroxisome, and cytosol.
## Post-Translational Modification
### N-linked glycosylation
It was found that there are several post-translational modifications that are performed on PRR32. These include several N-linked glycosylation sites that were predicted with high confidence. Glycosylation is known to play a part in cell-cell adhesion ( `a mechanism employed by cells of the immune system) via sugar-binding proteins. The graph illustrates predicted N-glyc sites across the protein chain
(x-axis represents protein length from N- to C-terminal). A position with a potential (vertical lines) crossing the threshold (horizontal line at 0.5) is predicted glycosylated.
# Homology and Evolution
A list was generated of orthologs using the NCBI (protein) blast for PRR32, as well as UCSC’s BLAT (BLAST-Like Alignment Tool. These search and analyzing engines generated orthologs that are 80+long. This list was then narrowed down to a list of 30 different species. From those 30 species, they were divided into certain portions. The first to be selected were the primates since they are the closest related species when it comes to genetics. The similarity generated when compared to humans was approximately 95-99%. Then, using the edit and resubmit option on Blast (proteins), I excluded all primates in order to widen the species selection. The BLAST search again yielded many mammals including Rabbit, Dog, Ferret, Rhino, and many more. These species’ similarity percentage was anywhere between 69%-89%. Next, to further diversify my species selection, again using the same method, I excluded all mammals from the BLAST sequencing. This time, there were absolutely no matches in the inquiry. This action was repeated a few more times and it seems that the PRR32 gene is only relevant in mammals. The google spreadsheet created below lists the selection of species and all important information such as, order, year of divergence, etc. One thing to be noted is that the protein sequences for PRR32 were highly conserved amongst closely related species of Homo sapiens such as the Chimpanzee, Gorilla, and Orangutan.
# Clinical Significance
## Amyotrophic lateral sclerosis
An experiment analyzed gene expression pattern in muscles from patients with amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN) compared to controls. Biopsied skeletal muscles from three ALS, three MMN and three control subjects had total RNA extracted and subjected to genome-wide gene expression analysis using Affymetrix GeneChip Exon 1.0 ST array. The most significant expression pattern differences were confirmed with RT-PCR in four additional ALS patients. Results showed that over 3000 genes were identified across the groups using q < 10%. Among 50 genes that were overexpressed only in the ALS group were: leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. No genes were significantly overexpressed in MMN alone. Underexpressed genes only in ALS included actinin αα3, fructose-1,6-bisphosphatase-2 and homeobox C10; whereas only in MMN: hemoglobin A1 and CXorf64. Ankyrin repeat domain-1 was overexpressed in both groups. Underexpressed genes in both groups included myosin light chain kinase-2, enolase-3 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-1. Validation analysis using RT-PCR confirmed the data for leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. In conclusion, there is differential tissue-specific gene expression in patients with ALS relative to MMN and controls. Further studies are necessary to evaluate the identified genes in larger patient groups and different tissues. | PRR32
PRR32 is a protein that in humans is encoded by the CXorf64 (Chromosome X Open Reading Frame 64) gene. It was also found that the homologs of the PRR32 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, and rat. It was also found through ncbi that 82 organisms have orthologs with human gene PRR323.[1]
PRR32 (CXorf64) seems to be involved with a group of genes over-expressed in ALS (Amyotrophic lateral sclerosis), evident from a study aiming to study gene expression patterns in muscles from patients with amyotrophic lateral sclerosis and multifocal motor neuropathy.[2]
# Gene
The gene is located on Chromosome X, at position Xq25, and is 2023 bases long (significantly small when compared to other genes). Its location is at the antisense (+) strand. As shown in the graphic below, it is flanked by upstream by the DKAF12l1 shown in green on the left and downstream by LOC10. CXorf64 is the blue column shown in the middle.[3]
## Transcript
CXorf64 has 1 exon which ultimately forms 1 transcript variant. This gene is expressed most in muscle tissue. There are no known isoforms in which CXorf64 is expressed.[4]
# Protein
## General Properties
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is marked by long alpha-helices localized to the end of the protein opposite the N- and C- terminal ends
## Expression
According to microarray-assessed tissue expression analysis by NCBI GEO, the gene CXorf64 has average expression levels in most tissues save for, prostate, and heart, fat, and endometrium which have relatively low levels of expression (~25th percentile of tissue gene expression) . Almost every microarray study determined very low levels of gene expression across all tissues assessed . This evidence prompted further analysis with other tools. While no tissue analysis was present on Allen Brain Atlas or genepaint, the Human Protein Atlas suggested that the gene was more highly expressed in heart, prostate, and a and fat tissues .
## Sub-cellular Location
It synthesizes in the cell cytoplasm and is predicted to localize in the mitochondria. It is predicted to localize in the nucleus, plasma membrane, extracellular, mitochondrion, peroxisome, and cytosol.
## Post-Translational Modification
### N-linked glycosylation
It was found that there are several post-translational modifications that are performed on PRR32. These include several N-linked glycosylation sites that were predicted with high confidence. Glycosylation is known to play a part in cell-cell adhesion ( `a mechanism employed by cells of the immune system) via sugar-binding proteins. The graph illustrates predicted N-glyc sites across the protein chain
(x-axis represents protein length from N- to C-terminal). A position with a potential (vertical lines) crossing the threshold (horizontal line at 0.5) is predicted glycosylated.[8]
# Homology and Evolution
A list was generated of orthologs using the NCBI (protein) blast for PRR32, as well as UCSC’s BLAT (BLAST-Like Alignment Tool. These search and analyzing engines generated orthologs that are 80+long. This list was then narrowed down to a list of 30 different species. From those 30 species, they were divided into certain portions. The first to be selected were the primates since they are the closest related species when it comes to genetics. The similarity generated when compared to humans was approximately 95-99%. Then, using the edit and resubmit option on Blast (proteins), I excluded all primates in order to widen the species selection. The BLAST search again yielded many mammals including Rabbit, Dog, Ferret, Rhino, and many more. These species’ similarity percentage was anywhere between 69%-89%. Next, to further diversify my species selection, again using the same method, I excluded all mammals from the BLAST sequencing. This time, there were absolutely no matches in the inquiry. This action was repeated a few more times and it seems that the PRR32 gene is only relevant in mammals. The google spreadsheet created below lists the selection of species and all important information such as, order, year of divergence, etc. One thing to be noted is that the protein sequences for PRR32 were highly conserved amongst closely related species of Homo sapiens such as the Chimpanzee, Gorilla, and Orangutan.
# Clinical Significance
## Amyotrophic lateral sclerosis
An experiment analyzed gene expression pattern in muscles from patients with amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN) compared to controls. Biopsied skeletal muscles from three ALS, three MMN and three control subjects had total RNA extracted and subjected to genome-wide gene expression analysis using Affymetrix GeneChip Exon 1.0 ST array. The most significant expression pattern differences were confirmed with RT-PCR in four additional ALS patients. Results showed that over 3000 genes were identified across the groups using q < 10%. Among 50 genes that were overexpressed only in the ALS group were: leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. No genes were significantly overexpressed in MMN alone. Underexpressed genes only in ALS included actinin αα3, fructose-1,6-bisphosphatase-2 and homeobox C10; whereas only in MMN: hemoglobin A1 and CXorf64. Ankyrin repeat domain-1 was overexpressed in both groups. Underexpressed genes in both groups included myosin light chain kinase-2, enolase-3 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-1. Validation analysis using RT-PCR confirmed the data for leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. In conclusion, there is differential tissue-specific gene expression in patients with ALS relative to MMN and controls. Further studies are necessary to evaluate the identified genes in larger patient groups and different tissues. | https://www.wikidoc.org/index.php/PRR32 | |
436f55a59859c8d570a77ce2520394592b92c6a9 | wikidoc | PRRT2 | PRRT2
Proline-rich transmembrane protein 2 is a protein that in humans is encoded by the PRRT2 gene.
# Structure and tissue distribution
This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages.
# Clinical significance
Mutations in this gene are associated with paroxysmal kinesigenic dyskinesia. Almost one third of sporadic PKC patients also carry PRRT2 mutations. | PRRT2
Proline-rich transmembrane protein 2 is a protein that in humans is encoded by the PRRT2 gene.[1]
# Structure and tissue distribution
This gene encodes a transmembrane protein containing a proline-rich domain in its N-terminal half. Studies in mice suggest that it is predominantly expressed in brain and spinal cord in embryonic and postnatal stages.[1]
# Clinical significance
Mutations in this gene are associated with paroxysmal kinesigenic dyskinesia.[2] Almost one third of sporadic PKC patients also carry PRRT2 mutations.[3] | https://www.wikidoc.org/index.php/PRRT2 | |
85ee91c86e6979bbb00fcf3905795a42331dd8e7 | wikidoc | PRRX1 | PRRX1
Paired related homeobox 1 is a protein that in humans is encoded by the PRRX1 gene.
# Function
The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription coactivator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns.
# Role in mesenchymal stem cell differentiation
Prrx1 expression is restricted to the mesoderm during embryonic development, and both Prrx1 and Prrx2 are expressed in mesenchymal tissues in adult mice. Mice that lack both Prrx1 and Prrx2 have profound defects in mesenchymal cell differentiation in the craniofacial region. Several recent studies demonstrate that PRRX1 can regulate differentiation of mesenchymal precursors. For example, PRRX1 inhibits adipogenesis by activating transforming growth factor-beta (TGF-beta) signaling, and also acts downstream of tumor necrosis factor-alpha to inhibit osteoblast differentiation. | PRRX1
Paired related homeobox 1 is a protein that in humans is encoded by the PRRX1 gene.[1][2]
# Function
The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription coactivator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns.[2]
# Role in mesenchymal stem cell differentiation
Prrx1 expression is restricted to the mesoderm during embryonic development, and both Prrx1 and Prrx2 are expressed in mesenchymal tissues in adult mice.[3][4][5][6][7] Mice that lack both Prrx1 and Prrx2 have profound defects in mesenchymal cell differentiation in the craniofacial region.[5][8] Several recent studies demonstrate that PRRX1 can regulate differentiation of mesenchymal precursors. For example, PRRX1 inhibits adipogenesis by activating transforming growth factor-beta (TGF-beta) signaling,[9] and also acts downstream of tumor necrosis factor-alpha to inhibit osteoblast differentiation.[10] | https://www.wikidoc.org/index.php/PRRX1 | |
bae1f25d115c71ea8470c24ae61b5e202692699e | wikidoc | PRSS8 | PRSS8
Prostasin is a protein that in humans is encoded by the PRSS8 gene.
This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. The proprotein is cleaved to produce a light chain and a heavy chain which are associated by a disulfide bond. It is active on peptide linkages involving the carboxyl group of lysine or arginine.
The protein is implicated in epithelial sodium channel regulation and may help regulate a variety of tissue functions that involve a sodium channel. | PRSS8
Prostasin is a protein that in humans is encoded by the PRSS8 gene.[1][2][3]
This gene encodes a trypsinogen, which is a member of the trypsin family of serine proteases. This enzyme is highly expressed in prostate epithelia and is one of several proteolytic enzymes found in seminal fluid. The proprotein is cleaved to produce a light chain and a heavy chain which are associated by a disulfide bond. It is active on peptide linkages involving the carboxyl group of lysine or arginine.
The protein is implicated in epithelial sodium channel regulation[4] and may help regulate a variety of tissue functions that involve a sodium channel.[5] | https://www.wikidoc.org/index.php/PRSS8 | |
2ad2c8fd4a8aa430a7b9e5c0ef409faea790aab2 | wikidoc | PSAT1 | PSAT1
Phosphoserine aminotransferase (PSA) also known as phosphohydroxythreonine aminotransferase (PSAT) is an enzyme that in humans is encoded by the PSAT1 gene.
The protein encoded by this gene is likely a phosphoserine aminotransferase, based on similarity to proteins in mouse, rabbit, and Drosophila. Alternative splicing of this gene results in two transcript variants encoding different isoforms.
# Clinical significance
Homozygous or compound heterozygous mutations in PSAT1 cause Neu-Laxova syndrome and phosphoserine aminotransferase deficiency.
# Model organisms
Model organisms have been used in the study of PSAT1 function. A conditional knockout mouse line, called Psat1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals. | PSAT1
Phosphoserine aminotransferase (PSA) also known as phosphohydroxythreonine aminotransferase (PSAT) is an enzyme that in humans is encoded by the PSAT1 gene.[1]
The protein encoded by this gene is likely a phosphoserine aminotransferase, based on similarity to proteins in mouse, rabbit, and Drosophila. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[1]
# Clinical significance
Homozygous or compound heterozygous mutations in PSAT1 cause Neu-Laxova syndrome[2] and phosphoserine aminotransferase deficiency.[3]
# Model organisms
Model organisms have been used in the study of PSAT1 function. A conditional knockout mouse line, called Psat1tm1a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty four tests were carried out on mutant mice and two significant abnormalities were observed.[6] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[6] | https://www.wikidoc.org/index.php/PSAT1 | |
847773418084bf652b2e3084ae21388c0ad98532 | wikidoc | PSIP1 | PSIP1
PC4 and SFRS1 interacting protein 1, also known as lens epithelium-derived growth factor (LEDGF/p75), dense fine speckles 70kD protein (DFS 70) or transcriptional coactivator p75/p52, is a protein that in humans is encoded by the PSIP1 gene.
# Function
PSIP1 has not been clearly linked to a specific cellular mechanism. The term LEDGF/p75 (Lens epithelium-derived growth factor) has entered common usage based on the initial characterization of PSIP1, however this is a misnomer, as the protein is present in most tissues and has no direct role in the development of lens epithelium. LEDGF/p75, a transcription coactivator, gained prominence as a host factor that assists HIV integration and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels. The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery. LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression. LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing, also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.
# Structure
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein. The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain, which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein. An isoform of the protein, LEDGF/p52, is produced by alternative splicing. LEDGF/p52 shares the N-terminal 325 amino acids of LEDGF/p75 but lacks the integrase-binding domain.
# Interactions
PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex. | PSIP1
PC4 and SFRS1 interacting protein 1, also known as lens epithelium-derived growth factor (LEDGF/p75), dense fine speckles 70kD protein (DFS 70) or transcriptional coactivator p75/p52, is a protein that in humans is encoded by the PSIP1 gene.[1][2]
# Function
PSIP1 has not been clearly linked to a specific cellular mechanism. The term LEDGF/p75 (Lens epithelium-derived growth factor) has entered common usage based on the initial characterization of PSIP1, however this is a misnomer, as the protein is present in most tissues and has no direct role in the development of lens epithelium. LEDGF/p75, a transcription coactivator, gained prominence as a host factor that assists HIV integration[3] and is probably the only integrase interactor whose knock-down severely affects the HIV integration levels.[4][5][6] The interaction between HIV integrase and human LEDGF/p75 is a promising target for anti-HIV drug discovery.[7] LEDGF/p75 recruits MLL complexes to HOX genes to regulate their expression.[8] LEDGF/p52 is shown to recruit splicing factors to H3K36 trimethylated chromatin to modulate alternative splicing,[9] also regulates HOTTIP lncRNA, which is shown to regulate HOX genes in cis.[10]
# Structure
LEDGF/p75 is a 60kDa, 530-amino-acid-long protein.[11] The N-terminal portion of the protein consists of a PWWP domain, a nuclear localization sequence, and two copies of the AT-hook DNA binding motif. The C-terminal portion of LEDGF/p75 contains a structure termed the integrase-binding domain,[12] which interacts with lentiviral integrase proteins as well as numerous cellular proteins. The N-terminal portion interacts strongly with chromatin, making LEDGF/p75 a constitutively nuclear protein. An isoform of the protein, LEDGF/p52, is produced by alternative splicing. LEDGF/p52 shares the N-terminal 325 amino acids of LEDGF/p75 but lacks the integrase-binding domain.
# Interactions
PSIP1 has been shown to interact with the proteins ASF/SF2, JPO2, Cdc7-Dbf4, and POGZ as well as the menin/MLL protein complex.[13][14] | https://www.wikidoc.org/index.php/PSIP1 | |
435b8d834207e05c54ee4980879c21b1fc58c668 | wikidoc | PSMA2 | PSMA2
Proteasome subunit alpha type-2 is a protein that in humans is encoded by the PSMA2 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Structure
## Protein expression
The gene PSMA2 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. Using FISH, the human gene HC3 (old nomenclature for PMSA2, 4.3kb with 3 exons) was mapped at chromosome band 6q27. The human protein proteasome subunit alpha type-2 is also known as 20S proteasome subunit alpha-2 (based on systematic nomenclature). The protein is 25.9 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 6.77.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological precesses. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
As a component of alpha ring, Proteasome subunit alpha type-2 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, alpha2 subunit plays an critical role in the assembly of 19S base and 20S. In a study using Saccharomyces cerevisiae proteasome core particle 20S and regulatory particle 19S (similar to human proteasome) base component to delineate the binding process between 19S and 20S, evidences showed that one 19S subunit, Rpt6, can insert its tail into the pocket formed by alpha2 and alpha3 subunit, facilitating the complex formation between 20S and 19S base component.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers. | PSMA2
Proteasome subunit alpha type-2 is a protein that in humans is encoded by the PSMA2 gene.[1][2][3] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Structure
## Protein expression
The gene PSMA2 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit.[3] Using FISH, the human gene HC3 (old nomenclature for PMSA2, 4.3kb with 3 exons) was mapped at chromosome band 6q27. The human protein proteasome subunit alpha type-2 is also known as 20S proteasome subunit alpha-2 (based on systematic nomenclature). The protein is 25.9 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 6.77.[4]
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[5][6]
# Function
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[6] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit.[7][8] The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[8][9] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological precesses. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
As a component of alpha ring, Proteasome subunit alpha type-2 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, alpha2 subunit plays an critical role in the assembly of 19S base and 20S. In a study using Saccharomyces cerevisiae proteasome core particle 20S and regulatory particle 19S (similar to human proteasome) base component to delineate the binding process between 19S and 20S, evidences showed that one 19S subunit, Rpt6, can insert its tail into the pocket formed by alpha2 and alpha3 subunit, facilitating the complex formation between 20S and 19S base component.[10]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [11] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[12] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[13][14] cardiovascular diseases,[15][16][17] inflammatory responses and autoimmune diseases,[18] and systemic DNA damage responses leading to malignancies.[19]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[20] Parkinson's disease[21] and Pick's disease,[22] Amyotrophic lateral sclerosis (ALS),[22] Huntington's disease,[21] Creutzfeldt–Jakob disease,[23] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[24] and several rare forms of neurodegenerative diseases associated with dementia.[25] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[26] ventricular hypertrophy[27] and Heart failure.[28] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[29] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[18] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[30] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[31] | https://www.wikidoc.org/index.php/PSMA2 | |
17b909d41d171f1fbc4e313a54b8e3521a97be64 | wikidoc | PSMA3 | PSMA3
Proteasome subunit alpha type-3 also known as macropain subunit C8 and proteasome component C8 is a protein that in humans is encoded by the PSMA3 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-3 contributes to the formation of heptameric alpha rings and substrate entrance gate.
# Structure
The human protein proteasome subunit alpha type-3 is 28.4 kDa in size and composed of 254 amino acids. The calculated theoretical pI of this protein is 5.08.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
A role of the proteasome subunit alpha type-3 has been linked in underlying mechanisms of human malignancies. It has been suggested that Cables1 as a novel p21 regulator through maintaining p21 stability and supporting the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21. In this process, Cables 1 mechanistically interferes the proteasome subunit alpha type-3 (PMSA3) hereby binding to p21 to induce cell death and inhibit cell proliferation.
# Interactions
PSMA3 has been shown to interact with
- CRYAB,
- PLK1,
- PSMA6, and
- Zif268. | PSMA3
Proteasome subunit alpha type-3 also known as macropain subunit C8 and proteasome component C8 is a protein that in humans is encoded by the PSMA3 gene.[1][2] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-3 contributes to the formation of heptameric alpha rings and substrate entrance gate.
# Structure
The human protein proteasome subunit alpha type-3 is 28.4 kDa in size and composed of 254 amino acids. The calculated theoretical pI of this protein is 5.08.[3]
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit.[6][7] The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease,[19] Creutzfeldt–Jakob disease,[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[22] and several rare forms of neurodegenerative diseases associated with dementia.[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[24] ventricular hypertrophy[25] and Heart failure.[26] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[27] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]
A role of the proteasome subunit alpha type-3 has been linked in underlying mechanisms of human malignancies. It has been suggested that Cables1 as a novel p21 regulator through maintaining p21 stability and supporting the model that the tumor-suppressive function of Cables1 occurs at least in part through enhancing the tumor-suppressive activity of p21. In this process, Cables 1 mechanistically interferes the proteasome subunit alpha type-3 (PMSA3) hereby binding to p21 to induce cell death and inhibit cell proliferation.[30]
# Interactions
PSMA3 has been shown to interact with
- CRYAB,[31]
- PLK1,[32]
- PSMA6,[33][34] and
- Zif268.[35] | https://www.wikidoc.org/index.php/PSMA3 | |
4ce100c7cfc571b7f1f1d81fce333a8dd6936826 | wikidoc | PSMA4 | PSMA4
Proteasome subunit alpha type-4 also known as macropain subunit C9, proteasome component C9, and 20S proteasome subunit alpha-3 is a protein that in humans is encoded by the PSMA4 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Structure
## Protein expression
The PSMA4 gene encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. The gene has 9 exons and locates at chromosome band 15q25.1. The human protein proteasome subunit alpha type-4 is 29.5 kDa in size and composed of 261 amino acids. The calculated theoretical pI of this protein is 6.97.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-4 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, this subunit plays an critical role in the assembly of 19S base and 20S. In a study using Saccharomyces cerevisiae proteasome core particle 20S and regulatory particle 19S (similar to human proteasome) base component to delineate the binding process between 19S and 20S, evidences showed that one 19S subunit, Rpt6, can insert its tail into the pocket formed by alpha2 and alpha3 subunit (based on systematic nomenclature), facilitating the complex formation between 20S and 19S base component.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
As genetic factors play an crucial role in the predisposition to cancer, genome-wide association studies (GWAS) have linked the chromosome 15q25.1 locus to the susceptibility of lung cancer and implicated the proteasome subunit alpha type-4 (PMSA4) as a candidate gene. A case-control study in lung cancer patients and controls in the Chinese Han population was investigated and suggested an association between PSMA4 and lung cancer. Furthermore, PMSA4 has also been implicated to be involved in the pathogenesis of ankylosing spondylitis (AS) and may therefore be a potential biomarker for clinical applications in AS.
# Interactions
PSMA4 has been shown to interact with PLK1. | PSMA4
Proteasome subunit alpha type-4 also known as macropain subunit C9, proteasome component C9, and 20S proteasome subunit alpha-3 is a protein that in humans is encoded by the PSMA4 gene.[1] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Structure
## Protein expression
The PSMA4 gene encodes a member of the peptidase T1A family, that is a 20S core alpha subunit.[2] The gene has 9 exons and locates at chromosome band 15q25.1. The human protein proteasome subunit alpha type-4 is 29.5 kDa in size and composed of 261 amino acids. The calculated theoretical pI of this protein is 6.97.[3]
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Function
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit.[6][7] The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-4 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, this subunit plays an critical role in the assembly of 19S base and 20S. In a study using Saccharomyces cerevisiae proteasome core particle 20S and regulatory particle 19S (similar to human proteasome) base component to delineate the binding process between 19S and 20S, evidences showed that one 19S subunit, Rpt6, can insert its tail into the pocket formed by alpha2 and alpha3 subunit (based on systematic nomenclature), facilitating the complex formation between 20S and 19S base component.[9]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [10] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[11] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[12][13] cardiovascular diseases,[14][15][16] inflammatory responses and autoimmune diseases,[17] and systemic DNA damage responses leading to malignancies.[18]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[19] Parkinson's disease[20] and Pick's disease,[21] Amyotrophic lateral sclerosis (ALS),[21] Huntington's disease,[20] Creutzfeldt–Jakob disease,[22] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[23] and several rare forms of neurodegenerative diseases associated with dementia.[24] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[25] ventricular hypertrophy[26] and Heart failure.[27] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[28] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[17] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[29] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[30]
As genetic factors play an crucial role in the predisposition to cancer, genome-wide association studies (GWAS) have linked the chromosome 15q25.1 locus to the susceptibility of lung cancer and implicated the proteasome subunit alpha type-4 (PMSA4) as a candidate gene. A case-control study in lung cancer patients and controls in the Chinese Han population was investigated and suggested an association between PSMA4 and lung cancer.[31] Furthermore, PMSA4 has also been implicated to be involved in the pathogenesis of ankylosing spondylitis (AS) and may therefore be a potential biomarker for clinical applications in AS.[32]
# Interactions
PSMA4 has been shown to interact with PLK1.[33] | https://www.wikidoc.org/index.php/PSMA4 | |
d990ab8e7fcff2aa7ff0b9bf5df7bc9740a71551 | wikidoc | PSMA5 | PSMA5
Proteasome subunit alpha type-5 also known as 20S proteasome subunit alpha-5 is a protein that in humans is encoded by the PSMA5 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, Proteasome subunit alpha type-5 contributes to the formation of heptameric alpha rings and substrate entrance gate.
# Structure
## Expression
The gene PSMA5 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. The gene has 9 exons and locates at chromosome band 1p13. The human protein proteasome subunit alpha type-5 is 26.5 kDa in size and composed of 241 amino acids. The calculated theoretical pI (isoelectric point) of this protein is 4.69.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Gene expression levels of the proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 patients with neuroendocrine pulmonary tumors and compared to controls. The study reviled that PSMB4 mRNA was significantly associated with proliferative activity of neuroendocrine pulmonary tumors. However, a role of PSMA5 was also indicated in neuroendocrine pulmonary tumors. The PSMA5 protein has further been associated with the biosynthesis of conjugated linoleum acid (CLA) in mammary tissue.
# Interactions
PSMA5 has been shown to interact with PLK1. | PSMA5
Proteasome subunit alpha type-5 also known as 20S proteasome subunit alpha-5 is a protein that in humans is encoded by the PSMA5 gene.[1][2] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, Proteasome subunit alpha type-5 contributes to the formation of heptameric alpha rings and substrate entrance gate.
# Structure
## Expression
The gene PSMA5 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit.[3] The gene has 9 exons and locates at chromosome band 1p13. The human protein proteasome subunit alpha type-5 is 26.5 kDa in size and composed of 241 amino acids. The calculated theoretical pI (isoelectric point) of this protein is 4.69.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit.[6][7] The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease,[19] Creutzfeldt–Jakob disease,[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[22] and several rare forms of neurodegenerative diseases associated with dementia.[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[24] ventricular hypertrophy[25] and Heart failure.[26] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[27] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]
Gene expression levels of the proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 patients with neuroendocrine pulmonary tumors and compared to controls. The study reviled that PSMB4 mRNA was significantly associated with proliferative activity of neuroendocrine pulmonary tumors.[30] However, a role of PSMA5 was also indicated in neuroendocrine pulmonary tumors. The PSMA5 protein has further been associated with the biosynthesis of conjugated linoleum acid (CLA) in mammary tissue.[31]
# Interactions
PSMA5 has been shown to interact with PLK1.[32] | https://www.wikidoc.org/index.php/PSMA5 | |
86eb487ea963d28d970aad56e09c979173d32154 | wikidoc | PSMA7 | PSMA7
Proteasome subunit alpha type-7 also known as 20S proteasome subunit alpha-4 is a protein that in humans is encoded by the PSMA7 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-7 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, this subunit plays an critical role in the assembly of 19S base and 20S. This particular subunit has been shown to interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. In addition, this subunit is involved in regulating hepatitis virus C internal ribosome entry site (IRES) activity, an activity essential for viral replication. This core alpha subunit is also involved in regulating the hypoxia-inducible factor-1alpha, a transcription factor important for cellular responses to oxygen tension. Recent study on underlying mechanisms of E3 ligase Parkin-related neurodegeneration identified this proteasome subunit as one of Parkin associating partner. The protein-protein interaction was initiated between the C-terminal domain of Parkin and C-terminal of subunit alpha4 (systematic nomenclature).
# Structure
## Expression
The gene PSMA7 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. This gene has 7 exons and locates at a chromosome band 20q13.33. Multiple isoforms of this subunit arising from alternative splicing may exist but alternative transcripts for only two isoforms have been defined. A pseudogene has been identified on chromosome 9.
The human protein Proteasome subunit alpha type-7 is 28 kDa in size and composed of 248 amino acids. The calculated theoretical pI (Isoelectric point) of this protein is 8.60.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Reports have shown that the proteasome subunit alpha type-7 (PSMA7) is overexpressed in colorectal cancer and associated with its hepatic metastasis. It was further reported that PSMA7 is associated with nucleotide-binding oligomerization domain-containing protein 1 (NOD1) as a negative regulator and may promote tumor growth by its inhibitory role on NOD1.
# Interactions
PSMA7 has been shown to interact with HIF1A and PLK1. | PSMA7
Proteasome subunit alpha type-7 also known as 20S proteasome subunit alpha-4 is a protein that in humans is encoded by the PSMA7 gene.[1][2] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex.
# Function
The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. As a component of alpha ring, proteasome subunit alpha type-7 contributes to the formation of heptameric alpha rings and substrate entrance gate. Importantly, this subunit plays an critical role in the assembly of 19S base and 20S. This particular subunit has been shown to interact specifically with the hepatitis B virus X protein, a protein critical to viral replication. In addition, this subunit is involved in regulating hepatitis virus C internal ribosome entry site (IRES) activity, an activity essential for viral replication. This core alpha subunit is also involved in regulating the hypoxia-inducible factor-1alpha, a transcription factor important for cellular responses to oxygen tension. Recent study on underlying mechanisms of E3 ligase Parkin-related neurodegeneration identified this proteasome subunit as one of Parkin associating partner. The protein-protein interaction was initiated between the C-terminal domain of Parkin and C-terminal of subunit alpha4 (systematic nomenclature).[3]
# Structure
## Expression
The gene PSMA7 encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. This gene has 7 exons and locates at a chromosome band 20q13.33. Multiple isoforms of this subunit arising from alternative splicing may exist but alternative transcripts for only two isoforms have been defined. A pseudogene has been identified on chromosome 9.[2]
The human protein Proteasome subunit alpha type-7 is 28 kDa in size and composed of 248 amino acids. The calculated theoretical pI (Isoelectric point) of this protein is 8.60.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Mechanism
Crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit.[6][7] The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease,[19] Creutzfeldt–Jakob disease,[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[22] and several rare forms of neurodegenerative diseases associated with dementia.[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[24] ventricular hypertrophy[25] and Heart failure.[26] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[27] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]
Reports have shown that the proteasome subunit alpha type-7 (PSMA7) is overexpressed in colorectal cancer and associated with its hepatic metastasis.[30][31] It was further reported that PSMA7 is associated with nucleotide-binding oligomerization domain-containing protein 1 (NOD1) as a negative regulator and may promote tumor growth by its inhibitory role on NOD1.[32]
# Interactions
PSMA7 has been shown to interact with HIF1A[33] and PLK1.[34] | https://www.wikidoc.org/index.php/PSMA7 | |
8b063a5e4d80dc7a7f3f5e25df8fc20948738c7c | wikidoc | PSMB1 | PSMB1
Proteasome subunit beta type-1 also known as 20S proteasome subunit beta-6 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB1 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-1, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The gene PSMB1 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is tightly linked to the TBP (TATA-binding protein) gene in human and in mouse, and is transcribed in the opposite orientation in both species. The gene has 6 exons and locates at chromosome band 6q27.
## Protein
The human protein proteasome subunit beta type-1 is 26.5 kDa in size and composed of 241 amino acids. The calculated theoretical pI of this protein is 8.27.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-1 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease,
Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
The proteasome subunit beta type-1 (also known as 20S proteasome subunit beta-6) is a protein encoded by the PSMB1 gene in humans and has been a subject of investigations in several clinical conditions. For instance, a mutated form of PSMB1 displayed an increased nuclear translocation, which resulted in the activation of transcription in adipocytes relevant in diabetes mellitus. Overall, the PSMB1 protein has been described in several forms of malignancies such as follicular lymphoma with an important mechanistic role in tumorigenesis. | PSMB1
Proteasome subunit beta type-1 also known as 20S proteasome subunit beta-6 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB1 gene.[1] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-1, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The gene PSMB1 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is tightly linked to the TBP (TATA-binding protein) gene in human and in mouse, and is transcribed in the opposite orientation in both species.[2] The gene has 6 exons and locates at chromosome band 6q27.
## Protein
The human protein proteasome subunit beta type-1 is 26.5 kDa in size and composed of 241 amino acids. The calculated theoretical pI of this protein is 8.27.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[3][4]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-1 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[4] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[5][6] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[6][7]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [8] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[9] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[10][11] cardiovascular diseases,[12][13][14] inflammatory responses and autoimmune diseases,[15] and systemic DNA damage responses leading to malignancies.[16]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[17] Parkinson's disease[18] and Pick's disease,[19]
Amyotrophic lateral sclerosis (ALS),[4] Huntington's disease,[18] Creutzfeldt–Jakob disease,[20] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[21] and several rare forms of neurodegenerative diseases associated with dementia.[22] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[23] ventricular hypertrophy[24] and Heart failure.[25] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[26] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[15] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[27] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[28]
The proteasome subunit beta type-1 (also known as 20S proteasome subunit beta-6) is a protein encoded by the PSMB1 gene in humans and has been a subject of investigations in several clinical conditions. For instance, a mutated form of PSMB1 displayed an increased nuclear translocation, which resulted in the activation of transcription in adipocytes relevant in diabetes mellitus.[29] Overall, the PSMB1 protein has been described in several forms of malignancies[30][31][32] such as follicular lymphoma[31] with an important mechanistic role in tumorigenesis.[33] | https://www.wikidoc.org/index.php/PSMB1 | |
5798d0ca3a72df113707ee88001635e0e2a55e5a | wikidoc | PSMB2 | PSMB2
Proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB2 gene. This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The gene PSMB2 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. The gene has 7 exons and locates at chromosome band 1p34.2.
## Protein
The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 201 amino acids. The calculated theoretical pI of this protein is 6.52.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
The proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4, a protein encoded by the PSMB2 gene in humans has shown to be stable in broncho alveolar cells (BAL) of the lung during certain clinical conditions such as interstitial lung disease and sarcoidosis (in parallel with RPL32). PSMB2 is therefore, a suitable reference gene for normalization in BAL cells in sarcoidosis, and other interstitial lung disease during clinical studies applying quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR. | PSMB2
Proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB2 gene.[1] This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The gene PSMB2 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit.[2] The gene has 7 exons and locates at chromosome band 1p34.2.
## Protein
The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 201 amino acids. The calculated theoretical pI of this protein is 6.52.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[3][4]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[4] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[5][6] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[6][7]
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [8] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[9] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[10][11] cardiovascular diseases,[12][13][14] inflammatory responses and autoimmune diseases,[15] and systemic DNA damage responses leading to malignancies.[16]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[17] Parkinson's disease[18] and Pick's disease,[19] Amyotrophic lateral sclerosis (ALS),[19] Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[20] and several rare forms of neurodegenerative diseases associated with dementia.[21] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[22] ventricular hypertrophy[23] and Heart failure.[24] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[25] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[15] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[26] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[27]
The proteasome subunit beta type-2 also known as 20S proteasome subunit beta-4, a protein encoded by the PSMB2 gene in humans has shown to be stable in broncho alveolar cells (BAL) of the lung during certain clinical conditions such as interstitial lung disease and sarcoidosis (in parallel with RPL32). PSMB2 is therefore, a suitable reference gene for normalization in BAL cells in sarcoidosis, and other interstitial lung disease during clinical studies applying quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR.[28] | https://www.wikidoc.org/index.php/PSMB2 | |
233983ef3a4c3561857bbdc5843afdd86f605c0b | wikidoc | PSMB3 | PSMB3
Proteasome subunit beta type-3, also known as 20S proteasome subunit beta-3, is a protein that in humans is encoded by the PSMB3 gene. This protein is one of the 17 essential subunits that contribute to the complete assembly of the 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognizes degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes.
# Structure
## Protein expression
The gene PSMB3 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. Pseudogenes have been identified on chromosomes 2 and 12. The gene has 6 exons and locates at chromosome band 17q12. The human protein proteasome subunit beta type-3 is 23 kDa in size and composed of 205 amino acids. The calculated theoretical pI of this protein is 6.14.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contain a proteolytic active site and have distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-3 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
# Interactions
PSMB3 has been shown to interact with PLK1. | PSMB3
Proteasome subunit beta type-3, also known as 20S proteasome subunit beta-3, is a protein that in humans is encoded by the PSMB3 gene.[1] This protein is one of the 17 essential subunits[2] that contribute to the complete assembly of the 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognizes degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes.
# Structure
## Protein expression
The gene PSMB3 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. Pseudogenes have been identified on chromosomes 2 and 12.[3] The gene has 6 exons and locates at chromosome band 17q12. The human protein proteasome subunit beta type-3 is 23 kDa in size and composed of 205 amino acids. The calculated theoretical pI of this protein is 6.14.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contain a proteolytic active site and have distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-3 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[6][7] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[21] and several rare forms of neurodegenerative diseases associated with dementia.[22] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[23] ventricular hypertrophy[24] and Heart failure.[25] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[26] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[27] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[28]
# Interactions
PSMB3 has been shown to interact with PLK1.[29] | https://www.wikidoc.org/index.php/PSMB3 | |
47b73ad6c5d19ac1f3b07ff407f87c571375b582 | wikidoc | PSMB4 | PSMB4
Proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB4 gene.
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
This gene PSMB4 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. The gene has 7 exons and locates at chromosome band 1q21.
## Protein
The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 219 amino acids. The calculated theoretical pI of this protein is 5.47.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-4 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has also been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Proteasomal subunit PSMB4 (proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7) has been suggested as a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. Additionally, gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumors and compared to controls and it was further revealed tha PSMB4 mRNA was significantly associated with the proliferative activity of neuroendocrine pulmonary tumors. Thus far, it appears that PSMB4 may have significant roles in underlying processes and mechanisms of malignancies.
# Interactions
PSMB4 has been shown to interact with Mothers against decapentaplegic homolog 1. | PSMB4
Proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB4 gene.[1]
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-2, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
This gene PSMB4 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit.[2] The gene has 7 exons and locates at chromosome band 1q21.
## Protein
The human protein proteasome subunit beta type-2 is 23 kDa in size and composed of 219 amino acids. The calculated theoretical pI of this protein is 5.47.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[3][4]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-4 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[4] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[5][6] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[6][7]
# Clinical significance
The proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. Recently, more effort has also been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [8] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[9] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[10][11] cardiovascular diseases,[12][13][14] inflammatory responses and autoimmune diseases,[15] and systemic DNA damage responses leading to malignancies.[16]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[17] Parkinson's disease[18] and Pick's disease,[19] Amyotrophic lateral sclerosis (ALS),[19] Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[20] and several rare forms of neurodegenerative diseases associated with dementia.[21] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[22] ventricular hypertrophy[23] and Heart failure.[24] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[25] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[15] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[26] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[27]
Proteasomal subunit PSMB4 (proteasome subunit beta type-4 also known as 20S proteasome subunit beta-7) has been suggested as a survival gene in an animal model of hepatocellular carcinoma and in glioblastoma cell lines. Additionally, gene expression levels of proteasomal subunits (PSMA1, PSMA5, PSMB4, PSMB5 and PSMD1) were investigated in 80 neuroendocrine pulmonary tumors and compared to controls and it was further revealed tha PSMB4 mRNA was significantly associated with the proliferative activity of neuroendocrine pulmonary tumors.[28] Thus far, it appears that PSMB4 may have significant roles in underlying processes and mechanisms of malignancies.
# Interactions
PSMB4 has been shown to interact with Mothers against decapentaplegic homolog 1.[29][30] | https://www.wikidoc.org/index.php/PSMB4 | |
bd20a926c46bfe3b44078a264b0e347636a028a5 | wikidoc | PSMB5 | PSMB5
Proteasome subunit beta type-5 as known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene. This protein is one of the 17 essential subunits (alpha subunits 1–7, constitutive beta subunits 1–7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Protein expression
The gene PSMB5 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. This catalytic subunit is not present in the immunoproteasome and is replaced by catalytic subunit beta5i (proteasome beta 8 subunit). The gene has 5 exons and locates at chromosome band 14q11.2. The human protein proteasome subunit beta type-5 is 22 kDa in size and composed of 204 amino acids. The calculated theoretical pI of this protein is 8.66.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
The 20S proteasome subunit beta-5 (systematic nomenclature) is originally expressed as a precursor with 263 amino acids. The fragment of 59 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta5 subunit of 20S complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
Radiation therapy is a critical modality in the treatment of cancer. Accordingly, the proteasome subunit alpha type-1 was examined as a strategy in radio sensitizing for the treatment of non-small cell lung carcinomas. Proteasome inhibition through the knockdown of PSMA1 resulting in loss of protein expression of the proteasome subunit alpha type-1 and the proteasome chymotrypsin-like activity and also in a loss of expression of PSMB5 protein (proteasome subunit beta type-5). A combination of PSMA1 knockdown in parallel with radiation therapy to treat non-small cell lung carcinoma resulted in an increased sensitivity of the tumor to radiation and improved tumor control. The study suggests that proteasome inhibition through PSMA1 knockdown is a promising strategy for non-small cell lung carcinomas radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes, and that the proteasome subunit beta type-5 may play a significant role in this process. | PSMB5
Proteasome subunit beta type-5 as known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene.[1][2][3] This protein is one of the 17 essential subunits (alpha subunits 1–7, constitutive beta subunits 1–7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide.[2] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Protein expression
The gene PSMB5 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. This catalytic subunit is not present in the immunoproteasome and is replaced by catalytic subunit beta5i (proteasome beta 8 subunit).[3] The gene has 5 exons and locates at chromosome band 14q11.2. The human protein proteasome subunit beta type-5 is 22 kDa in size and composed of 204 amino acids. The calculated theoretical pI of this protein is 8.66.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, and beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[4][5]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[5] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[6][7] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[7][8]
The 20S proteasome subunit beta-5 (systematic nomenclature) is originally expressed as a precursor with 263 amino acids. The fragment of 59 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta5 subunit of 20S complex.[9]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [10] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[11] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[12][13] cardiovascular diseases,[14][15][16] inflammatory responses and autoimmune diseases,[17] and systemic DNA damage responses leading to malignancies.[18]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[19] Parkinson's disease[20] and Pick's disease,[21] Amyotrophic lateral sclerosis (ALS),[21] Huntington's disease,[20] Creutzfeldt–Jakob disease,[22] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[23] and several rare forms of neurodegenerative diseases associated with dementia.[24] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[25] ventricular hypertrophy[26] and Heart failure.[27] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[28] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[29] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[30] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[31]
Radiation therapy is a critical modality in the treatment of cancer. Accordingly, the proteasome subunit alpha type-1 was examined as a strategy in radio sensitizing for the treatment of non-small cell lung carcinomas. Proteasome inhibition through the knockdown of PSMA1 resulting in loss of protein expression of the proteasome subunit alpha type-1 and the proteasome chymotrypsin-like activity and also in a loss of expression of PSMB5 protein (proteasome subunit beta type-5). A combination of PSMA1 knockdown in parallel with radiation therapy to treat non-small cell lung carcinoma resulted in an increased sensitivity of the tumor to radiation and improved tumor control.[32] The study suggests that proteasome inhibition through PSMA1 knockdown is a promising strategy for non-small cell lung carcinomas radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes, and that the proteasome subunit beta type-5 may play a significant role in this process.[32] | https://www.wikidoc.org/index.php/PSMB5 | |
617116649825df1bb948729745dfddc47ac8fea9 | wikidoc | PSMB6 | PSMB6
Proteasome subunit beta type-6 also known as 20S proteasome subunit beta-1 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB6 gene.
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-6, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Caspase-like" activity and is capable of cleaving after acidic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The human gene contains 6 exons and is located at chromosome band 17p13.
## Protein
The human protein proteasome subunit beta type-6 is 22 kDa in size and composed of 205 amino acids. The calculated theoretical pI of this protein is 4.91.
The 20S proteasome subunit beta-1 (systematic nomenclature) is originally expressed as a precursor with 239 amino acids. The fragment of 34 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta1 subunit is cleaved, forming the mature beta1 subunit of 20S complex.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
The gene PSMB6 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. This catalytic subunit is not present in the immunoproteasome and is replaced by catalytic inducible subunit beta1i (proteasome beta 9 subunit).
The proteasomes are an pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Compromised proteasome complex assembly leads to reduced proteolytic activities and accumulation of damaged or misfolded protein species. Such protein accumulation has become phenotypic characteristics of neurodegenerative diseases, cardiovascular diseases, and systemic DNA damage responses.
The function of this protein is supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has also been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to important clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
As aforementioned, the proteasome subunit beta type-6, also known as 20S proteasome subunit beta-1 is a protein that is encoded by the PSMB6 gene in humans. A clinically important role of the PSMB6 protein has been mainly found in malignancies. For instance, pharmacological drug therapy with Periplocin in the treatment of rheumatoid arthritis, is also found to inhibit lung cancer in both in-vivo and in-vitro experimental models. Accordingly, the protein profile changes of human lung cancer cell lines A549 in response to periplocin treatment were investigated using proteomics approaches (2-DE combined with MS/MS) in conjuction with Western blot analysis to verify the changed proteins. Using immunoblot analysis followed by STRING bioinformatics analysis, it was revealed that Periplocin can inhibited growth of lung cancer by down-regulating proteins, such as ATP5A1, EIF5A, ALDH1 and PSMB6. Thus, the proteasome subunit beta type-6 (PSMB6) appears to have a significant role in molecular mechanisms underlying the anti-cancer effects of periplocin on lung cancer cells. A proteomic study, analyzing differentially expressed UPS proteins in a rat model of chronic hypoxic pulmonary hypertension which is characterized by sustained elevation of pulmonary vascular resistance that results in vascular remodeling, revealed a significant association with the PSMB6 protein. Chronic hypoxia up-regulated the proteasome activity and the proliferation of pulmonary artery smooth muscle cells, which may be related to an increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. Thus, there may be an essential role of the proteasome during chronic hypoxic pulmonary hypertension. | PSMB6
Proteasome subunit beta type-6 also known as 20S proteasome subunit beta-1 (based on systematic nomenclature) is a protein that in humans is encoded by the PSMB6 gene.[1][2][3]
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-6, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Caspase-like" activity and is capable of cleaving after acidic residues of peptide.[4] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The human gene contains 6 exons and is located at chromosome band 17p13.
## Protein
The human protein proteasome subunit beta type-6 is 22 kDa in size and composed of 205 amino acids. The calculated theoretical pI of this protein is 4.91.
The 20S proteasome subunit beta-1 (systematic nomenclature) is originally expressed as a precursor with 239 amino acids. The fragment of 34 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta1 subunit is cleaved, forming the mature beta1 subunit of 20S complex.[5]
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[6][7]
# Function
The gene PSMB6 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. This catalytic subunit is not present in the immunoproteasome and is replaced by catalytic inducible subunit beta1i (proteasome beta 9 subunit).[3]
The proteasomes are an pivotal component for the Ubiquitin-Proteasome System (UPS)[8] and corresponding cellular Protein Quality Control (PQC). Compromised proteasome complex assembly leads to reduced proteolytic activities and accumulation of damaged or misfolded protein species. Such protein accumulation has become phenotypic characteristics of neurodegenerative diseases,[9][10] cardiovascular diseases,[11][12][13] and systemic DNA damage responses.[14]
The function of this protein is supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[7] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[15][16] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[16][17]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has also been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to important clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [8] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[18] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[9][10] cardiovascular diseases,[11][12][13] inflammatory responses and autoimmune diseases,[19] and systemic DNA damage responses leading to malignancies.[14]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[20] Parkinson's disease[21] and Pick's disease,[22] Amyotrophic lateral sclerosis (ALS),[22] Huntington's disease,[21] Creutzfeldt–Jakob disease,[23] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[24] and several rare forms of neurodegenerative diseases associated with dementia.[25] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[26] ventricular hypertrophy[27] and Heart failure.[28] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[29] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[19] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[30] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[31]
As aforementioned, the proteasome subunit beta type-6, also known as 20S proteasome subunit beta-1 is a protein that is encoded by the PSMB6 gene in humans. A clinically important role of the PSMB6 protein has been mainly found in malignancies. For instance, pharmacological drug therapy with Periplocin in the treatment of rheumatoid arthritis, is also found to inhibit lung cancer in both in-vivo and in-vitro experimental models. Accordingly, the protein profile changes of human lung cancer cell lines A549 in response to periplocin treatment were investigated using proteomics approaches (2-DE combined with MS/MS) in conjuction with Western blot analysis to verify the changed proteins.[32] Using immunoblot analysis followed by STRING bioinformatics analysis, it was revealed that Periplocin can inhibited growth of lung cancer by down-regulating proteins, such as ATP5A1, EIF5A, ALDH1 and PSMB6. Thus, the proteasome subunit beta type-6 (PSMB6) appears to have a significant role in molecular mechanisms underlying the anti-cancer effects of periplocin on lung cancer cells.[32] A proteomic study, analyzing differentially expressed UPS proteins in a rat model of chronic hypoxic pulmonary hypertension which is characterized by sustained elevation of pulmonary vascular resistance that results in vascular remodeling, revealed a significant association with the PSMB6 protein.[33] Chronic hypoxia up-regulated the proteasome activity and the proliferation of pulmonary artery smooth muscle cells, which may be related to an increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. Thus, there may be an essential role of the proteasome during chronic hypoxic pulmonary hypertension.[34] | https://www.wikidoc.org/index.php/PSMB6 | |
e732c9eed917b38f7c20339ef7acd3a38947ab77 | wikidoc | PSMB7 | PSMB7
Proteasome subunit beta type-7 as known as 20S proteasome subunit beta-2 is a protein that in humans is encoded by the PSMB7 gene.
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Trypsin-like" activity and is capable of cleaving after basic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The human PSMB7 gene has 8 exons and locates at chromosome band 9q34.11-q34.12.
## Protein
The gene PSMB7 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. Expression of this catalytic subunit (beta 2, according to systematic nomenclature) is downregulated by gamma interferon due to an alternatively elevated expression of inducible subunit beta2i, which leads to augmented incorporation of beta2i instead of beta2 into the final assembled 20S complex. The human protein proteasome subunit beta type-7 is 25 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 5.61.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
The 20S proteasome subunit beta-2 (systematic nomenclature) is originally expressed as a precursor with 277 amino acids. The fragment of 43 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta2 subunit of 20S complex. During the basal assembly, and proteolytic processing is required to generate a mature subunit. This subunit is not present in the immunoproteasome and is replaced by catalytic subunit 2i (proteasome beta 10 subunit).
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
The PSMB7 protein has a variety of clinically relevant constituents. For instance, in breast cancer cells, a high expression level of the PSMB7 protein suggests a shorter survival than in cells with a lower expression level. This interesting finding indicates that the PSMB7 protein may be used as a clinical prognostic biomarker in breast cancer. The same study also suggested that the PSMB7 protein is involved in anthracycline resistance, which is an antibiotic derived from streptomyces bacteria and used as an anticancer chemotherapy for leukemias, lymphomas, breast cancer, uterine, ovarian and lung cancers. Furthermore, the PSMB7 protein may also be involved in the resistance to 5-fluoro uracil (5-FU) therapy. Targeting the PSMB7 gene, to down-regulate PSMB7 protein, may overcome resistance to 5-FU and thus a possible new approach to treat hepatocellular carcinoma with this chemotherapeutic drug. High PSMB7 expression is an unfavourable prognostic marker in breast cancer. In this, survival of resistant breast cancer cell lines decreased after doxorubicin or paclitaxel treatment when PSMB7 was knocked down by RNA interference. These results were validated in 1592 microarray samples: patients with high PSMB7 expression had a significantly shorter survival than patients with low expression. Knockdown of the PSMB7 gene may also induce autophagy in cardiomyocytes. | PSMB7
Proteasome subunit beta type-7 as known as 20S proteasome subunit beta-2 is a protein that in humans is encoded by the PSMB7 gene.[1][2]
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Trypsin-like" activity and is capable of cleaving after basic residues of peptide.[1] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.
# Structure
## Gene
The human PSMB7 gene has 8 exons and locates at chromosome band 9q34.11-q34.12.
## Protein
The gene PSMB7 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit in the proteasome. Expression of this catalytic subunit (beta 2, according to systematic nomenclature) is downregulated by gamma interferon due to an alternatively elevated expression of inducible subunit beta2i, which leads to augmented incorporation of beta2i instead of beta2 into the final assembled 20S complex.[2] The human protein proteasome subunit beta type-7 is 25 kDa in size and composed of 234 amino acids. The calculated theoretical pI of this protein is 5.61.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[3][4]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[4] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[5][6] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[6][7]
The 20S proteasome subunit beta-2 (systematic nomenclature) is originally expressed as a precursor with 277 amino acids. The fragment of 43 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta2 subunit of 20S complex.[8] During the basal assembly, and proteolytic processing is required to generate a mature subunit. This subunit is not present in the immunoproteasome and is replaced by catalytic subunit 2i (proteasome beta 10 subunit).
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [9] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[10] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[11][12] cardiovascular diseases,[13][14][15] inflammatory responses and autoimmune diseases,[16] and systemic DNA damage responses leading to malignancies.[17]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[18] Parkinson's disease[19] and Pick's disease,[20] Amyotrophic lateral sclerosis (ALS),[20] Huntington's disease,[19] Creutzfeldt–Jakob disease,[21] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[22] and several rare forms of neurodegenerative diseases associated with dementia.[23] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[24] ventricular hypertrophy[25] and Heart failure.[26] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[27] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[16] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[28] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[29]
The PSMB7 protein has a variety of clinically relevant constituents. For instance, in breast cancer cells, a high expression level of the PSMB7 protein suggests a shorter survival than in cells with a lower expression level.[30] This interesting finding indicates that the PSMB7 protein may be used as a clinical prognostic biomarker in breast cancer.[30] The same study also suggested that the PSMB7 protein is involved in anthracycline resistance, which is an antibiotic derived from streptomyces bacteria and used as an anticancer chemotherapy for leukemias, lymphomas, breast cancer, uterine, ovarian and lung cancers.[31] Furthermore, the PSMB7 protein may also be involved in the resistance to 5-fluoro uracil (5-FU) therapy. Targeting the PSMB7 gene, to down-regulate PSMB7 protein, may overcome resistance to 5-FU and thus a possible new approach to treat hepatocellular carcinoma with this chemotherapeutic drug.[32] High PSMB7 expression is an unfavourable prognostic marker in breast cancer.[30] In this, survival of resistant breast cancer cell lines decreased after doxorubicin or paclitaxel treatment when PSMB7 was knocked down by RNA interference. These results were validated in 1592 microarray samples: patients with high PSMB7 expression had a significantly shorter survival than patients with low expression. Knockdown of the PSMB7 gene may also induce autophagy in cardiomyocytes.[33] | https://www.wikidoc.org/index.php/PSMB7 | |
69580d864ae057c4b2054effa5811e565fca4fe6 | wikidoc | PSMB8 | PSMB8
Proteasome subunit beta type-8 as known as 20S proteasome subunit beta-5i is a protein that in humans is encoded by the PSMB8 gene.
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 (systematic nomenclature) can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.
# Structure
## Gene
This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit.
The human PSMB8 gene has 7 exons and locates at chromosome band 6p21.3.
## Protein structure
The human protein proteasome subunit beta type-8 is 23 kDa in size and composed of 204 amino acids. The calculated theoretical pI of this protein is 7.59.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
The 20S proteasome subunit beta-5i (systematic nomenclature) is originally expressed as a precursor with 276 amino acids. The fragment of 72 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5i subunit is cleaved, forming the mature beta5i subunit of 20S complex. During the basal assembly, and proteolytic processing is required to generate a mature subunit. The subunit beta5i only presents in the immunoproteasome and is replaced by subunit beta5(proteasome beta 5 subunit) in constitutive 20S proteasome complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes. The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
The PSMB8 protein has a significant clinical role in autoimmune diseases and inflammatory reactions. For instance, patients with a homozygous missense mutation (G197V) in the immunoproteasome subunit, β type 8 (PSMB8) suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was also highly expressed, and there was a reduced expression of PSMB8. Furthermore, downregulation of PSMB8 also inhibited the differentiation of murine and human adipocytes in vitro, while an injection of siRNA against Psmb8 in mouse skin could reduce adipocyte tissue volume. Thus, PSMB8 may be an essential component and regulator not only for inflammation, but also in the differentiation of adipocytes, hereby indicating that immunoproteasomes may have pleiotropic functions to maintain the homeostasis of a variety of cell types. Subsequently, in addition to autoimmune diseases the PSMB8 protein also has been linked in the diagnosis of lipodystrophy syndrome. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly through PSMB8. They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis, and Nakajo-Nishimura syndrome, a distinct inherited inflammatory and wasting disease that is originated from Japan. Patients with Nakajo-Nishimura syndrome, develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint contractures. | PSMB8
Proteasome subunit beta type-8 as known as 20S proteasome subunit beta-5i is a protein that in humans is encoded by the PSMB8 gene.[1][2][3]
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide.[4] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 (systematic nomenclature) can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.[5]
# Structure
## Gene
This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit.[3]
The human PSMB8 gene has 7 exons and locates at chromosome band 6p21.3.
## Protein structure
The human protein proteasome subunit beta type-8 is 23 kDa in size and composed of 204 amino acids. The calculated theoretical pI of this protein is 7.59.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[6][7]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[7] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[8][9] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[9][10]
The 20S proteasome subunit beta-5i (systematic nomenclature) is originally expressed as a precursor with 276 amino acids. The fragment of 72 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5i subunit is cleaved, forming the mature beta5i subunit of 20S complex.[11] During the basal assembly, and proteolytic processing is required to generate a mature subunit. The subunit beta5i only presents in the immunoproteasome and is replaced by subunit beta5(proteasome beta 5 subunit) in constitutive 20S proteasome complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [12] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[13] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[14][15] cardiovascular diseases,[16][17][18] inflammatory responses and autoimmune diseases,[19] and systemic DNA damage responses leading to malignancies.[20]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[21] Parkinson's disease[22] and Pick's disease,[23] Amyotrophic lateral sclerosis (ALS),[23] Huntington's disease,[22] Creutzfeldt–Jakob disease,[24] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[25] and several rare forms of neurodegenerative diseases associated with dementia.[26] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[27] ventricular hypertrophy[28] and Heart failure.[29] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[30] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[19] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[31] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32]
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[33][34] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
The PSMB8 protein has a significant clinical role in autoimmune diseases and inflammatory reactions. For instance, patients with a homozygous missense mutation (G197V) in the immunoproteasome subunit, β type 8 (PSMB8) suffered from autoinflammatory responses that included recurrent fever and nodular erythema together with lipodystrophy. This mutation increased assembly intermediates of immunoproteasomes, resulting in decreased proteasome function and ubiquitin-coupled protein accumulation in the patient's tissues. In the patient's skin and B cells, IL-6 was also highly expressed, and there was a reduced expression of PSMB8. Furthermore, downregulation of PSMB8 also inhibited the differentiation of murine and human adipocytes in vitro, while an injection of siRNA against Psmb8 in mouse skin could reduce adipocyte tissue volume. Thus, PSMB8 may be an essential component and regulator not only for inflammation, but also in the differentiation of adipocytes, hereby indicating that immunoproteasomes may have pleiotropic functions to maintain the homeostasis of a variety of cell types.[35] Subsequently, in addition to autoimmune diseases the PSMB8 protein also has been linked in the diagnosis of lipodystrophy syndrome.[36] Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly through PSMB8. They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis,[36][37] and Nakajo-Nishimura syndrome,[38] a distinct inherited inflammatory and wasting disease that is originated from Japan. Patients with Nakajo-Nishimura syndrome, develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint contractures.[39] | https://www.wikidoc.org/index.php/PSMB8 | |
1b43c973ae2128db44d0dea6c02543d55349cf41 | wikidoc | PSMB9 | PSMB9
Proteasome subunit beta type-9 as known as 20S proteasome subunit beta-1i is a protein that in humans is encoded by the PSMB9 gene.
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Trypsin-like" activity and is capable of cleaving after basic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 (systematic nomenclature) can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.
# Structure
## Gene
The gene PSMB9 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding different isoforms have been identified; both isoforms are processed to yield the same mature subunit. The human PSMB9 gene has 6 exons and locates at chromosome band 6p21.3.
## Protein
The human protein proteasome subunit beta type-9 is 21 kDa in size and composed of 199 amino acids. The calculated theoretical pI of this protein is 4.80.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber. Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process. 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.
The 20S proteasome subunit beta-5i (systematic nomenclature) is originally expressed as a precursor with 276 amino acids. The fragment of 72 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta5i subunit of 20S complex. During the basal assembly, and proteolytic processing is required to generate a mature subunit. The subunit beta5i only presents in the immunoproteasome and is replaced by subunit beta5(proteasome beta 5 subunit) in constitutive 20S proteasome complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes. The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
The clinical relevance of the PSMB9 protein can be found mostly in the areas of infectious diseases, autoimmune diseases and oncology. For instance, it has been verified that mRNA coding for PSMB9 (together with CFD, MAGED1, PRDX4 and FCGR3B) is differentially expressed between patients who developed clinical symptoms associated with the mild disease type of Dengue fever, and patients who showed clinical symptoms associated with severe Dengue. The study suggests that this gene expression panel may serve as biomarkers of clinical prognosis in Dengue hemorrhagic fever. Further studies also indicate a role for PMSB9, in a panel with 9 other genes (Zbp1, Mx2, Irf7, Lfi47, Tapbp, Timp1, Trafd1, Tap2) in the development of influenza vaccines, and in the diagnosis of autoimmune disease Sjogren syndrome in conjunction with 18 other genes (EPSTI1, IFI44, IFI44L, IFIT1, IFIT2, IFIT3, MX1, OAS1, SAMD9L, STAT1, HERC5, EV12B, CD53, SELL, HLA-DQA1, PTPRC, B2M, and TAP2). With regards to oncology, PSMB9 in conjunction with other genes that are involved with immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA) may form a comprehensive assessment of the clinical outcome in epithelial ovarian carcinoma tumor methylation assessments. The study suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for high-grade serous epithelial ovarian carcinomas. | PSMB9
Proteasome subunit beta type-9 as known as 20S proteasome subunit beta-1i is a protein that in humans is encoded by the PSMB9 gene.[1][2][3]
This protein is one of the 17 essential subunits (alpha subunits 1-7, constitutive beta subunits 1-7, and inducible subunits including beta1i, beta2i, beta5i) that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "Trypsin-like" activity and is capable of cleaving after basic residues of peptide.[4] The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. The constitutive subunit beta1, beta2, and beta 5 (systematic nomenclature) can be replaced by their inducible counterparts beta1i, 2i, and 5i when cells are under the treatment of interferon-γ. The resulting proteasome complex becomes the so-called immunoproteasome. An essential function of the modified proteasome complex, the immunoproteasome, is the processing of numerous MHC class-I restricted T cell epitopes.[5]
# Structure
## Gene
The gene PSMB9 encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 1 (proteasome beta 6 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding different isoforms have been identified; both isoforms are processed to yield the same mature subunit.[3] The human PSMB9 gene has 6 exons and locates at chromosome band 6p21.3.
## Protein
The human protein proteasome subunit beta type-9 is 21 kDa in size and composed of 199 amino acids. The calculated theoretical pI of this protein is 4.80.
## Complex assembly
The proteasome is a multicatalytic proteinase complex with a highly ordered 20S core structure. This barrel-shaped core structure is composed of 4 axially stacked rings of 28 non-identical subunits: the two end rings are each formed by 7 alpha subunits, and the two central rings are each formed by 7 beta subunits. Three beta subunits (beta1, beta2, beta5) each contains a proteolytic active site and has distinct substrate preferences. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway.[6][7]
# Function
Protein functions are supported by its tertiary structure and its interaction with associating partners. As one of 28 subunits of 20S proteasome, protein proteasome subunit beta type-2 contributes to form a proteolytic environment for substrate degradation. Evidences of the crystal structures of isolated 20S proteasome complex demonstrate that the two rings of beta subunits form a proteolytic chamber and maintain all their active sites of proteolysis within the chamber.[7] Concomitantly, the rings of alpha subunits form the entrance for substrates entering the proteolytic chamber. In an inactivated 20S proteasome complex, the gate into the internal proteolytic chamber are guarded by the N-terminal tails of specific alpha-subunit. This unique structure design prevents random encounter between proteolytic active sites and protein substrate, which makes protein degradation a well-regulated process.[8][9] 20S proteasome complex, by itself, is usually functionally inactive. The proteolytic capacity of 20S core particle (CP) can be activated when CP associates with one or two regulatory particles (RP) on one or both side of alpha rings. These regulatory particles include 19S proteasome complexes, 11S proteasome complex, etc. Following the CP-RP association, the confirmation of certain alpha subunits will change and consequently cause the opening of substrate entrance gate. Besides RPs, the 20S proteasomes can also be effectively activated by other mild chemical treatments, such as exposure to low levels of sodium dodecylsulfate (SDS) or NP-14.[9][10]
The 20S proteasome subunit beta-5i (systematic nomenclature) is originally expressed as a precursor with 276 amino acids. The fragment of 72 amino acids at peptide N-terminal is essential for proper protein folding and subsequent complex assembly. At the end-stage of complex assembly, the N-terminal fragment of beta5 subunit is cleaved, forming the mature beta5i subunit of 20S complex.[11] During the basal assembly, and proteolytic processing is required to generate a mature subunit. The subunit beta5i only presents in the immunoproteasome and is replaced by subunit beta5(proteasome beta 5 subunit) in constitutive 20S proteasome complex.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [12] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[13] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[14][15] cardiovascular diseases,[16][17][18] inflammatory responses and autoimmune diseases,[19] and systemic DNA damage responses leading to malignancies.[20]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[21] Parkinson's disease[22] and Pick's disease,[23] Amyotrophic lateral sclerosis (ALS),[23] Huntington's disease,[22] Creutzfeldt–Jakob disease,[24] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[25] and several rare forms of neurodegenerative diseases associated with dementia.[26] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[27] ventricular hypertrophy[28] and Heart failure.[29] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[30] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[19] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[31] Lastly, autoimmune disease patients with SLE, Sjögren syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[32]
During the antigen processing for the major histocompatibility complex (MHC) class-I, the proteasome is the major degradation machinery that degrades the antigen and present the resulting peptides to cytotoxic T lymphocytes.[33][34] The immunoproteasome has been considered playing a critical role in improving the quality and quantity of generated class-I ligands.
The clinical relevance of the PSMB9 protein can be found mostly in the areas of infectious diseases, autoimmune diseases and oncology. For instance, it has been verified that mRNA coding for PSMB9 (together with CFD, MAGED1, PRDX4 and FCGR3B) is differentially expressed between patients who developed clinical symptoms associated with the mild disease type of Dengue fever, and patients who showed clinical symptoms associated with severe Dengue. The study suggests that this gene expression panel may serve as biomarkers of clinical prognosis in Dengue hemorrhagic fever.[35] Further studies also indicate a role for PMSB9, in a panel with 9 other genes (Zbp1, Mx2, Irf7, Lfi47, Tapbp, Timp1, Trafd1, Tap2) in the development of influenza vaccines,[36] and in the diagnosis of autoimmune disease Sjogren syndrome in conjunction with 18 other genes (EPSTI1, IFI44, IFI44L, IFIT1, IFIT2, IFIT3, MX1, OAS1, SAMD9L, STAT1, HERC5, EV12B, CD53, SELL, HLA-DQA1, PTPRC, B2M, and TAP2).[37] With regards to oncology, PSMB9 in conjunction with other genes that are involved with immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA) may form a comprehensive assessment of the clinical outcome in epithelial ovarian carcinoma tumor methylation assessments. The study suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for high-grade serous epithelial ovarian carcinomas.[38] | https://www.wikidoc.org/index.php/PSMB9 | |
16ffd81f95386702e237daaae88b4c64e75c1566 | wikidoc | PSMC1 | PSMC1
26S protease regulatory subunit 4, also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that in humans is encoded by the PSMC1 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2 (this protein), Rpt3, Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC1 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. The human PSMC1 gene has 11 exons and locates at chromosome band 14q32.11.
# Protein
The human protein 26S protease regulatory subunit 4 is 49kDa in size and composed of 440 amino acids. The calculated theoretical pI of this protein is 526S protease regulatory subunit 5.68. One expression isoform is generated by alternative splicing, in which 1-73 of the amino acid sequence is missing.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis. Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases, cardiovascular diseases, inflammatory responses and autoimmune diseases, and systemic DNA damage responses leading to malignancies.
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Pick's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, Creutzfeldt–Jakob disease, and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies and several rare forms of neurodegenerative diseases associated with dementia. As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury, ventricular hypertrophy and Heart failure. Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies. Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO). Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors. Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.
In humans the 26S protease regulatory subunit 4', also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that is encoded by the PSMC1 gene. This protein and is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Megakaryocytes that were isolated from mice deficient for PSMC1 failed to produce pro platelets. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA. It appears that proteasome function, through an underlying mechanisms involving PSMC1, is critical for thrombopoiesis. Furthermore, inhibition of RhoA signaling in this process may be a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.
# Interactions
PSMC1 has been shown to interact with PSMD2 and PSMC2. | PSMC1
26S protease regulatory subunit 4, also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that in humans is encoded by the PSMC1 gene.[1][2] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex.[3] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2 (this protein), Rpt3, Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[3]
# Gene
The gene PSMC1 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. The human PSMC1 gene has 11 exons and locates at chromosome band 14q32.11.
# Protein
The human protein 26S protease regulatory subunit 4 is 49kDa in size and composed of 440 amino acids. The calculated theoretical pI of this protein is 526S protease regulatory subunit 5.68. One expression isoform is generated by alternative splicing, in which 1-73 of the amino acid sequence is missing.[4]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[5][6][7][8][9][10] These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[3]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[11] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[12][13] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[14][15]
# Clinical significance
The Proteasome and its subunits are of clinical significance for at least two reasons: (1) a compromised complex assembly or a dysfunctional proteasome can be associated with the underlying pathophysiology of specific diseases, and (2) they can be exploited as drug targets for therapeutic interventions. More recently, more effort has been made to consider the proteasome for the development of novel diagnostic markers and strategies. An improved and comprehensive understanding of the pathophysiology of the proteasome should lead to clinical applications in the future.
The proteasomes form a pivotal component for the Ubiquitin-Proteasome System (UPS) [16] and corresponding cellular Protein Quality Control (PQC). Protein ubiquitination and subsequent proteolysis and degradation by the proteasome are important mechanisms in the regulation of the cell cycle, cell growth and differentiation, gene transcription, signal transduction and apoptosis.[17] Subsequently, a compromised proteasome complex assembly and function lead to reduced proteolytic activities and the accumulation of damaged or misfolded protein species. Such protein accumulation may contribute to the pathogenesis and phenotypic characteristics in neurodegenerative diseases,[18][19] cardiovascular diseases,[20][21][22] inflammatory responses and autoimmune diseases,[23] and systemic DNA damage responses leading to malignancies.[24]
Several experimental and clinical studies have indicated that aberrations and deregulations of the UPS contribute to the pathogenesis of several neurodegenerative and myodegenerative disorders, including Alzheimer's disease,[25] Parkinson's disease[26] and Pick's disease,[27] Amyotrophic lateral sclerosis (ALS),[27] Huntington's disease,[26] Creutzfeldt–Jakob disease,[28] and motor neuron diseases, polyglutamine (PolyQ) diseases, Muscular dystrophies[29] and several rare forms of neurodegenerative diseases associated with dementia.[30] As part of the Ubiquitin-Proteasome System (UPS), the proteasome maintains cardiac protein homeostasis and thus plays a significant role in cardiac Ischemic injury,[31] ventricular hypertrophy[32] and Heart failure.[33] Additionally, evidence is accumulating that the UPS plays an essential role in malignant transformation. UPS proteolysis plays a major role in responses of cancer cells to stimulatory signals that are critical for the development of cancer. Accordingly, gene expression by degradation of transcription factors, such as p53, c-Jun, c-Fos, NF-κB, c-Myc, HIF-1α, MATα2, STAT3, sterol-regulated element-binding proteins and androgen receptors are all controlled by the UPS and thus involved in the development of various malignancies.[34] Moreover, the UPS regulates the degradation of tumor suppressor gene products such as adenomatous polyposis coli (APC) in colorectal cancer, retinoblastoma (Rb). and von Hippel-Lindau tumor suppressor (VHL), as well as a number of proto-oncogenes (Raf, Myc, Myb, Rel, Src, Mos, Abl). The UPS is also involved in the regulation of inflammatory responses. This activity is usually attributed to the role of proteasomes in the activation of NF-κB which further regulates the expression of pro inflammatory cytokines such as TNF-α, IL-β, IL-8, adhesion molecules (ICAM-1, VCAM-1, P-selectin) and prostaglandins and nitric oxide (NO).[23] Additionally, the UPS also plays a role in inflammatory responses as regulators of leukocyte proliferation, mainly through proteolysis of cyclines and the degradation of CDK inhibitors.[35] Lastly, autoimmune disease patients with SLE, Sjogren's syndrome and rheumatoid arthritis (RA) predominantly exhibit circulating proteasomes which can be applied as clinical biomarkers.[36]
In humans the 26S protease regulatory subunit 4', also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that is encoded by the PSMC1 gene.[1][2] This protein and is one of the 19 essential subunits of a complete assembled 19S proteasome complex.[3] Megakaryocytes that were isolated from mice deficient for PSMC1 failed to produce pro platelets. The failure to produce proplatelets in proteasome-inhibited megakaryocytes was due to upregulation and hyperactivation of the small GTPase, RhoA. It appears that proteasome function, through an underlying mechanisms involving PSMC1, is critical for thrombopoiesis. Furthermore, inhibition of RhoA signaling in this process may be a potential strategy to treat thrombocytopenia in bortezomib-treated multiple myeloma patients.[37]
# Interactions
PSMC1 has been shown to interact with PSMD2[38][39] and PSMC2.[39][40] | https://www.wikidoc.org/index.php/PSMC1 | |
fa570febd9d78b6cc3338cef668671b821c861d0 | wikidoc | PSMC2 | PSMC2
26S protease regulatory subunit 7, also known as 26S proteasome AAA-ATPase subunit Rpt1, is an enzyme that in humans is encoded by the PSMC2 gene This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits (Rpt1 (this protein), Rpt2, Rpt3, Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC2 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with several of the basal transcription factors so, in addition to participation in proteasome functions, this subunit may participate in the regulation of transcription. This subunit may also compete with PSMC3 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. The human PSMC2 gene has 13 exons and locates at chromosome band 7q22.1-q22.3.
# Protein
The human protein 26S protease regulatory subunit 7 is 48.6kDa in size and composed of 433 amino acids. The calculated theoretical pI of this protein is 526S protease regulatory subunit 5.71. One expression isoform is generated by alternative splicing, in which 1–137 of the amino acid sequence is missing.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1–6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S
regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 (this protein) and Rpt2, Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.
# Interactions
PSMC2 has been shown to interact with:
- NDC80,
- PSMC1,
- PSMC4, and
- PSMD5. | PSMC2
26S protease regulatory subunit 7, also known as 26S proteasome AAA-ATPase subunit Rpt1, is an enzyme that in humans is encoded by the PSMC2 gene[1][2][3] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex.[4] Six 26S proteasome AAA-ATPase subunits (Rpt1 (this protein), Rpt2, Rpt3, Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[4]
# Gene
The gene PSMC2 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with several of the basal transcription factors so, in addition to participation in proteasome functions, this subunit may participate in the regulation of transcription. This subunit may also compete with PSMC3 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex.[3] The human PSMC2 gene has 13 exons and locates at chromosome band 7q22.1-q22.3.
# Protein
The human protein 26S protease regulatory subunit 7 is 48.6kDa in size and composed of 433 amino acids. The calculated theoretical pI of this protein is 526S protease regulatory subunit 5.71. One expression isoform is generated by alternative splicing, in which 1–137 of the amino acid sequence is missing.[5]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1–6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[6][7][8][9][10][11] These 19S
regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 (this protein) and Rpt2, Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[4]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[12] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[13][14] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[15][16]
# Interactions
PSMC2 has been shown to interact with:
- NDC80,[17]
- PSMC1,[18][19]
- PSMC4,[19][20] and
- PSMD5.[18][21] | https://www.wikidoc.org/index.php/PSMC2 | |
eedbc135627c5d5567e5d4e0d34e122394fd3980 | wikidoc | PSMC3 | PSMC3
26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5 (this protein), and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC3 encodes one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9. The human PSMC3 gene has 12 exons and locates at chromosome band 11p11.2.
# Protein
The human protein 26S protease regulatory subunit 6A is 49kDa in size and composed of 439 amino acids. The calculated theoretical pI of this protein is 5.68.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5 (this protein), Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring. Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.
# Interactions
PSMC3 has been shown to interact with PSMC5 and Von Hippel-Lindau tumor suppressor. | PSMC3
26S protease regulatory subunit 6A, also known as 26S proteasome AAA-ATPase subunit Rpt5, is an enzyme that in humans is encoded by the PSMC3 gene.[1][2] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex[3] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5 (this protein), and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[3]
# Gene
The gene PSMC3 encodes one of the ATPase subunits, a member of the triple-A family of ATPases that have chaperone-like activity. This subunit may compete with PSMC2 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. A pseudogene has been identified on chromosome 9.[4] The human PSMC3 gene has 12 exons and locates at chromosome band 11p11.2.
# Protein
The human protein 26S protease regulatory subunit 6A is 49kDa in size and composed of 439 amino acids. The calculated theoretical pI of this protein is 5.68.[5]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[6][7][8][9][10][11] These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5 (this protein), Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[3]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[12] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[13][14] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[15][16] Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.[17]
# Interactions
PSMC3 has been shown to interact with PSMC5[18] and Von Hippel-Lindau tumor suppressor.[19] | https://www.wikidoc.org/index.php/PSMC3 | |
dd37e0c0edc01551f8889c11cc5a2e0f60b6d712 | wikidoc | PSMC4 | PSMC4
26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3,is an enzyme that in humans is encoded by the PSMC4 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3 (this protein), Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC4 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with an orphan member of the nuclear hormone receptor superfamily highly expressed in liver, and with gankyrin, a liver oncoprotein. Two transcript variants encoding different isoforms have been identified. The human PSMC3 gene has 11 exons and locates at chromosome band 19q13.11-q13.13.
# Protein
The human protein 26S protease regulatory subunit 6B is 47kDa in size and composed of 418 amino acids. The calculated theoretical pI of this protein is 5.09.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3 (this protein), and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
In addition, evidences indicated that the C-terminus of Rpt3 was required for cellular assembly of this subunit into 26 S proteasome.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring. Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.
# Interactions
PSMC4 has been shown to interact with:
- PSMC2,
- PSMC5,
- PSMD10, and
- PSMD13. | PSMC4
26S protease regulatory subunit 6B, also known as 26S proteasome AAA-ATPase subunit Rpt3,is an enzyme that in humans is encoded by the PSMC4 gene.[1][2][3] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex[4] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3 (this protein), Rpt4, Rpt5, and Rpt6) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[4]
# Gene
The gene PSMC4 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with an orphan member of the nuclear hormone receptor superfamily highly expressed in liver, and with gankyrin, a liver oncoprotein. Two transcript variants encoding different isoforms have been identified.[3] The human PSMC3 gene has 11 exons and locates at chromosome band 19q13.11-q13.13.
# Protein
The human protein 26S protease regulatory subunit 6B is 47kDa in size and composed of 418 amino acids. The calculated theoretical pI of this protein is 5.09.[5]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[6][7][8][9][10][11] These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3 (this protein), and Rpn14/PAAAF1 to Rpt6, respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[4]
In addition, evidences indicated that the C-terminus of Rpt3 was required for cellular assembly of this subunit into 26 S proteasome.[12]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[13] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[14][15] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[16][17] Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.[18]
# Interactions
PSMC4 has been shown to interact with:
- PSMC2,[19][20]
- PSMC5,[19][21]
- PSMD10,[19][21][22] and
- PSMD13.[19] | https://www.wikidoc.org/index.php/PSMC4 | |
ced626f5f4948147ff8782113c0872cfa49f50f2 | wikidoc | PSMC5 | PSMC5
26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5, and Rpt6 (this protein)) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.
# Gene
The gene PSMC5 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha. The human PSMC5 gene has 13 exons and locates at chromosome band 17q23.3.
# Protein
The human protein 26S protease regulatory subunit 8 is 45.6kDa in size and composed of 406 amino acids. The calculated theoretical pI of this protein is 8.23.
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently. These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6 (this protein), respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP. Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring. Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.
# Interactions
PSMC5 has been shown to interact with:
- PSMC3,
- PSMC4,
- Sp1 transcription factor, and
- XPB. | PSMC5
26S protease regulatory subunit 8, also known as 26S proteasome AAA-ATPase subunit Rpt6, is an enzyme that in humans is encoded by the PSMC5 gene.[1][2][3] This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex[4] Six 26S proteasome AAA-ATPase subunits (Rpt1, Rpt2, Rpt3, Rpt4, Rpt5, and Rpt6 (this protein)) together with four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13) form the base sub complex of 19S regulatory particle for proteasome complex.[4]
# Gene
The gene PSMC5 encodes one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. In addition to participation in proteasome functions, this subunit may participate in transcriptional regulation since it has been shown to interact with the thyroid hormone receptor and retinoid X receptor-alpha.[3] The human PSMC5 gene has 13 exons and locates at chromosome band 17q23.3.
# Protein
The human protein 26S protease regulatory subunit 8 is 45.6kDa in size and composed of 406 amino acids. The calculated theoretical pI of this protein is 8.23.[5]
# Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, Rpn10, and Rpn13). Thus, 26S protease regulatory subunit 4 (Rpt2) is an essential component of forming the base subcomplex of 19S regulatory particle. For the assembly of 19S base sub complex, four sets of pivotal assembly chaperons (Hsm3/S5b, Nas2/P27, Nas6/P28, and Rpn14/PAAF1, nomenclature in yeast/mammals) were identified by four groups independently.[6][7][8][9][10][11] These 19S regulatory particle base-dedicated chaperons all binds to individual ATPase subunits through the C-terminal regions. For example, Hsm3/S5b binds to the subunit Rpt1 and Rpt2 (this protein), Nas2/p27 to Rpt5, Nas6/p28 to Rpt3, and Rpn14/PAAAF1 to Rpt6 (this protein), respectively. Subsequently, three intermediate assembly modules are formed as following, the Nas6/p28-Rpt3-Rpt6-Rpn14/PAAF1 module, the Nas2/p27-Rpt4-Rpt5 module, and the Hsm3/S5b-Rpt1-Rpt2-Rpn2 module. Eventually, these three modules assemble together to form the heterohexameric ring of 6 Atlases with Rpn1. The final addition of Rpn13 indicates the completion of 19S base sub complex assembly.[4]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[12] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex.
The ATPases subunits assemble into a six-membered ring with a sequence of Rpt1–Rpt5–Rpt4–Rpt3–Rpt6–Rpt2, which interacts with the seven-membered alpha ring of 20S core particle and eastablishs an asymmetric interface between the 19S RP and the 20S CP.[13][14] Three C-terminal tails with HbYX motifs of distinct Rpt ATPases insert into pockets between two defined alpha subunits of the CP and regulate the gate opening of the central channels in the CP alpha ring.[15][16] Evidence showed that ATPase subunit Rpt5, along with other ubuiqintinated 19S proteasome subunits (Rpn13, Rpn10) and the deubiquitinating enzyme Uch37, can be ubiquitinated in situ by proteasome-associating ubiquitination enzymes. Ubiquitination of proteasome subunits can regulates proteasomal activity in response to the alteration of cellular ubiquitination levels.[17]
# Interactions
PSMC5 has been shown to interact with:
- PSMC3,[18]
- PSMC4,[19][20]
- Sp1 transcription factor,[21][22] and
- XPB.[23] | https://www.wikidoc.org/index.php/PSMC5 |
Subsets and Splits