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1dd84e814938732e14934c8503704b82be1b4e8b | wikidoc | Senex | Senex
Senex is Latin for old man. In Ancient Rome, the title of Senex was only awarded to elderly men with families who had good standing in their village.
# Jungian Psychology
In Jungian analytical psychology, examples of the senex archetype in a positive form include the wise old man or wizard. The senex may also appear in a negative form as a devouring father (e.g. Ouranos, Cronus) or a doddering fool.
The antithetical archetype, or enantiodromic opposite, of the senex is the Puer Aeternus.
# Senex in literature
Two stock characters of theater are the senex amans, an old man unsuitably in love with a much younger woman, and the senex iratus, an old man who irrationally opposes the love of the young couple.
Senex is also the name of a wise old fara, a subcellular creature inside a mitochondrion, in the novel A Wind in the Door by Madeleine L'Engle (1973, ISBN 0-374-38443-6). | Senex
Senex is Latin for old man. In Ancient Rome, the title of Senex was only awarded to elderly men with families who had good standing in their village.
# Jungian Psychology
In Jungian analytical psychology, examples of the senex archetype in a positive form include the wise old man or wizard. The senex may also appear in a negative form as a devouring father (e.g. Ouranos, Cronus) or a doddering fool.
The antithetical archetype, or enantiodromic opposite, of the senex is the Puer Aeternus.
# Senex in literature
Two stock characters of theater are the senex amans, an old man unsuitably in love with a much younger woman, and the senex iratus, an old man who irrationally opposes the love of the young couple.[1]
Senex is also the name of a wise old fara, a subcellular creature inside a mitochondrion, in the novel A Wind in the Door by Madeleine L'Engle (1973, ISBN 0-374-38443-6). | https://www.wikidoc.org/index.php/Senex | |
327701a555a4a1ee467aada5ae80bcfd8bf80500 | wikidoc | Serum | Serum
# Overview
Serum (Latin for "whey") may refer to:
- Blood plasma, with clotting factors removed
- Serous fluid, any clear bodily fluid
- Truth serum, a general term for sedative drug or unspecified drug that is likely to make people tell truth or divulge information
- Medication, derived from an animal's blood or serous fluid, often involving:
Antibody, protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses
Antivenom, biological product used in the treatment of venomous bites or stings
Antiviral drug, used specifically for treating viral infections
Antidote, substance which can counteract a form of poisoning
- Antibody, protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses
- Antivenom, biological product used in the treatment of venomous bites or stings
- Antiviral drug, used specifically for treating viral infections
- Antidote, substance which can counteract a form of poisoning
# Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.
ar:مصل
de:Serum
no:Serum | Serum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Serum (Latin for "whey") may refer to:
- Blood plasma, with clotting factors removed
- Serous fluid, any clear bodily fluid
- Truth serum, a general term for sedative drug or unspecified drug that is likely to make people tell truth or divulge information
- Medication, derived from an animal's blood or serous fluid, often involving:
Antibody, protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses
Antivenom, biological product used in the treatment of venomous bites or stings
Antiviral drug, used specifically for treating viral infections
Antidote, substance which can counteract a form of poisoning
- Antibody, protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses
- Antivenom, biological product used in the treatment of venomous bites or stings
- Antiviral drug, used specifically for treating viral infections
- Antidote, substance which can counteract a form of poisoning
# Acknowledgements
The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.
ar:مصل
de:Serum
no:Serum
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Serum | |
52c8b2d6a7c6df06dfe3549a3d3df4ec48e55fde | wikidoc | Servo | Servo
Servo may refer to:
- Servomechanism, or servo, a device used to provide control of a desired operation through the use of feedback
- Servo drive, a special electric amplifier used to power electric servo motors
- Tom Servo, a fictional character from the television series Mystery Science Theater 3000
- SERVO Magazine, a monthly robotics publication.
Servo may also be:
- A multipurpose tool used by Gary Seven in the Star Trek episode Assignment: Earth
- Servotronic, speed-dependent power steering
- Australian slang term for a petrol station
- A character in the television series Superhuman Samurai Syber-Squad
- A non-playable character from computer game The Sims: Livin' Large
- A playable character from the expansion pack The Sims 2: Open for Business
- A song by The Brian Jonestown Massacre from the album Give It Back! | Servo
Servo may refer to:
- Servomechanism, or servo, a device used to provide control of a desired operation through the use of feedback
- Servo drive, a special electric amplifier used to power electric servo motors
- Tom Servo, a fictional character from the television series Mystery Science Theater 3000
- SERVO Magazine, a monthly robotics publication.
Servo may also be:
- A multipurpose tool used by Gary Seven in the Star Trek episode Assignment: Earth
- Servotronic, speed-dependent power steering
- Australian slang term for a petrol station
- A character in the television series Superhuman Samurai Syber-Squad
- A non-playable character from computer game The Sims: Livin' Large
- A playable character from the expansion pack The Sims 2: Open for Business
- A song by The Brian Jonestown Massacre from the album Give It Back!
Template:Disambig
Template:WS | https://www.wikidoc.org/index.php/Servo | |
944b6f6c023761d0eb4d9e53390ab819e9d559cc | wikidoc | Shame | Shame
Shame is the consciousness or awareness of dishonor, disgrace, or condemnation. Genuine shame is associated with genuine dishonor, disgrace, or condemnation. False shame is associated with false condemnation as in the double-bind form of false shaming; "he brought what we did to him upon himself". Therapist John Bradshaw calls shame the "emotion that lets us know we are finite".
# Characterizing shame
## Shame vs. guilt
There is no standard distinction between shame and guilt. The cultural anthropologist Ruth Benedict describes shame as a violation of cultural or social values while feelings of guilt arise from violations of internal values. It is possible to feel ashamed of thought or behavior that no one knows about as well as feeling guilty about actions that gain the approval of others. However, in Facing Shame, therapists Fossum and Mason state "While guilt is a painful feeling of regret and responsibility for one's actions, shame is a painful feeling about oneself as a person." Shame is needed to establish limits, in childhood, since young children are unable to associate cause and effect by themselves. However, as children become better able to judge their own actions, guilt becomes the conscience former. Although, in general, guilt guides adult consciences, intrinsic shame is often present in adults too.
## Shame vs. embarrassment
Shame differs from embarrassment in that it does not necessarily involve public humiliation: one can feel shame for an act known only to oneself, but in order to be embarrassed, one's actions must be revealed to others. Also, shame carries the connotation of a response to qualities that are considered morally wrong, whereas one can be embarrassed regarding actions that are morally neutral but socially unacceptable. Another view of shame and embarrassment is that the two emotions lie on a continuum and only differ in intensity. The wish to sink into the ground and disappear from view, to hide oneself from eyes that witness one's embarrassment or humiliation is common to both.
## Toxic shame
Psychologists often use the term "toxic" shame to describe false, and therefore, pathological shame. Therapist John Bradshaw states that toxic shame is induced, inside children, by all forms of child abuse. Incest and other forms of child sexual abuse can cause particularly severe toxic shame. Toxic shame often induces what is known as complex trauma in children who cannot cope with toxic shaming as it occurs and who dissociate the shame until it is possible to cope with.
Shamery (and shaming) is often associated with torture (see the psychology of torture). It is also a central feature of punishment, shunning, or ostracism. In addition, shame is often seen in victims of child neglect, child abuse and a host of other crimes against children. Parental incest is considered by child psychologists to be the ultimate form of shaming.
## Religious shame
In the Milgram experiment, described in the book Obedience to Authority, pp. 48-49, Stanley Milgram described one of a very few individuals in the entire series of experiments who was able to successfully resist authority without experiencing feelings of shame. This subject, a professor of religion, explained that his reason for being able to resist unjust authority with equanimity came from his religious faith. The subject explained that "If one has as one's ultimate authority ... then it trivializes human authority." Milgram wrote that "the answer for this man lies in the repudiation of authority, not in the substitution of good -- that is divine -- authority for bad."
## Vicarious shame
Psychologists recently introduced the notion of vicarious shame, which refers to the experience of shame on behalf of another person. Individuals vary in their tendency to experience vicarious shame, which is related to neuroticism and to the tendency to experience personal shame. Extremely shame-prone people might even experience vicarious shame even to an increased degree, in other words: shame on behalf of another person who is already feeling shame on behalf of a third party (or possibly on behalf of the individual proper).
# Shame in society
Shame is considered one aspect of socialization in all societies.
Shame is enshrouded in legal precedent as a pillar of punishment and ostensible correction.
Shame has been linked to narcissism in the psychoanalytic literature. It is one of the most intense emotions. The individual experiencing shame may feel totally despicable, worthless and feel that there is no redemption.
According to the anthropologist Ruth Benedict, cultures may be classified by their emphasis of using either shame or guilt to regulate the social activities of their members.
Shared opinions and expected behaviours that cause the feeling of shame (as well as an associated reproval) if violated by an individual are in any case proven to be very efficient in guiding behaviour in a group or society.
Shame is a common form of control used by those people who commit relational aggression. It is an important weapon in marriage, family, and church settings. It is also used in the workplace as a form of overt social control or aggression.
# Shame campaign
A shame campaign is a tactic in which particular individuals are singled out because of their behavior or suspected crimes, often by marking them publicly.
In the Philippines, Mayor Alfredo Lim popularized such tactics during his term as mayor of Manila. On July 1, 1997, he began a controversial "spray paint shame campaign” in an effort to stop drug use. He and his team sprayed bright red paint on two hundred squatter houses whose residents had been charged, but not yet convicted, of selling prohibited substances. Officials of other municipalities, emboldened by Lim’s campaign, began conceiving their own anti-crime shame strategies.
Lim’s shame campaign generated much publicity, and many questioned the legality and humaneness of singling out unconvicted suspects. Former Senator Rene A. Saguisag, a member of Movement for Brotherhood, Integrity and Nationalism, Inc. (MABINI), issued a public statement condemning Lim’s policy: "The shame campaign violated presumption of innocence because it transgresses due process…" In January 2000, the 14th Division of the Court of Appeals ruled the policy as "invalid and unconstitutional."
In January 2005, Metro Manila Development Authority Chair Bayani Fernando announced a "wet rags shame campaign" to target commuters who wait for rides in the middle of the streets. The MMDA traffic enforcers planned to punish jaywalkers by driving by in service vehicles and splashing them with wet rags attached to poles. Sound trucks were to drive ahead and warn pedestrians of their approach; those who refused to comply with traffic regulations were to have wet rags dropped on their heads.
Sen. Richard Gordon disagreed with the shame tactic, saying such a way of disciplining pedestrians is a "return to Grade One." He added that the campaign might work for a time but would end up being futile. Rep. Vincent Crisologo of Ilocos Sur, a known critic of Fernando, said the MMDA chief was resorting to martial law tactics. Rep. Rozzano Rufino Biazon of Muntinlupa City, criticized the plan: "It only shows that the MMDA looks at people as animals who should be herded like cattle instead of using reason to make them follow the law… it is an admission that its personnel assigned to the thoroughfares are not doing their job."
Chairman Fernando, unfazed by criticisms, proceeded with the campaign.
In 2005, Tony Kwok, Hong Kong’s former corruption chief, suggested that the Philippine government should carry out a shame campaign to eliminate political corruption. A consultant of the Philippines’ Office of the Ombudsman, Kwok said, "This is what you need, a shame campaign. You have to let the politicians know that corruption is a high-risk crime." Kwok cited Hong Kong’s use of TV advertisements to discourage governmental misconduct. He added, "The best way is through enforcement and education." | Shame
Template:Emotion
Shame is the consciousness or awareness of dishonor, disgrace, or condemnation. Genuine shame is associated with genuine dishonor, disgrace, or condemnation. False shame is associated with false condemnation as in the double-bind form of false shaming; "he brought what we did to him upon himself". Therapist John Bradshaw calls shame the "emotion that lets us know we are finite".[1]
# Characterizing shame
## Shame vs. guilt
There is no standard distinction between shame and guilt. The cultural anthropologist Ruth Benedict describes shame as a violation of cultural or social values while feelings of guilt arise from violations of internal values. It is possible to feel ashamed of thought or behavior that no one knows about as well as feeling guilty about actions that gain the approval of others. However, in Facing Shame, therapists Fossum and Mason state "While guilt is a painful feeling of regret and responsibility for one's actions, shame is a painful feeling about oneself as a person." Shame is needed to establish limits, in childhood, since young children are unable to associate cause and effect by themselves. However, as children become better able to judge their own actions, guilt becomes the conscience former. Although, in general, guilt guides adult consciences, intrinsic shame is often present in adults too.
## Shame vs. embarrassment
Shame differs from embarrassment in that it does not necessarily involve public humiliation: one can feel shame for an act known only to oneself, but in order to be embarrassed, one's actions must be revealed to others. Also, shame carries the connotation of a response to qualities that are considered morally wrong, whereas one can be embarrassed regarding actions that are morally neutral but socially unacceptable. Another view of shame and embarrassment is that the two emotions lie on a continuum and only differ in intensity. The wish to sink into the ground and disappear from view, to hide oneself from eyes that witness one's embarrassment or humiliation is common to both.[citation needed]
## Toxic shame
Psychologists often use the term "toxic" shame to describe false, and therefore, pathological shame. Therapist John Bradshaw states that toxic shame is induced, inside children, by all forms of child abuse. Incest and other forms of child sexual abuse can cause particularly severe toxic shame. Toxic shame often induces what is known as complex trauma in children who cannot cope with toxic shaming as it occurs and who dissociate the shame until it is possible to cope with.[citation needed]
Shamery (and shaming) is often associated with torture (see the psychology of torture). It is also a central feature of punishment, shunning, or ostracism. In addition, shame is often seen in victims of child neglect, child abuse and a host of other crimes against children. Parental incest is considered by child psychologists to be the ultimate form of shaming.[citation needed]
## Religious shame
Template:POV-section
In the Milgram experiment, described in the book Obedience to Authority, pp. 48-49, Stanley Milgram described one of a very few individuals in the entire series of experiments who was able to successfully resist authority without experiencing feelings of shame. This subject, a professor of religion, explained that his reason for being able to resist unjust authority with equanimity came from his religious faith. The subject explained that "If one has [God] as one's ultimate authority ... then it trivializes human authority." Milgram wrote that "the answer for this man lies in the repudiation of authority, not in the substitution of good -- that is[,] divine -- authority for bad."
## Vicarious shame
Psychologists recently introduced the notion of vicarious shame, which refers to the experience of shame on behalf of another person. Individuals vary in their tendency to experience vicarious shame, which is related to neuroticism and to the tendency to experience personal shame. Extremely shame-prone people might even experience vicarious shame even to an increased degree, in other words: shame on behalf of another person who is already feeling shame on behalf of a third party (or possibly on behalf of the individual proper).
# Shame in society
Shame is considered one aspect of socialization in all societies.
Shame is enshrouded in legal precedent as a pillar of punishment and ostensible correction.
Shame has been linked to narcissism in the psychoanalytic literature. It is one of the most intense emotions. The individual experiencing shame may feel totally despicable, worthless and feel that there is no redemption.
According to the anthropologist Ruth Benedict, cultures may be classified by their emphasis of using either shame or guilt to regulate the social activities of their members.
Shared opinions and expected behaviours that cause the feeling of shame (as well as an associated reproval) if violated by an individual are in any case proven to be very efficient in guiding behaviour in a group or society.
Shame is a common form of control used by those people who commit relational aggression. It is an important weapon in marriage, family, and church settings. It is also used in the workplace as a form of overt social control or aggression.
# Shame campaign
A shame campaign is a tactic in which particular individuals are singled out because of their behavior or suspected crimes, often by marking them publicly.
In the Philippines, Mayor Alfredo Lim popularized such tactics during his term as mayor of Manila. On July 1, 1997, he began a controversial "spray paint shame campaign” in an effort to stop drug use. He and his team sprayed bright red paint on two hundred squatter houses whose residents had been charged, but not yet convicted, of selling prohibited substances. Officials of other municipalities, emboldened by Lim’s campaign, began conceiving their own anti-crime shame strategies.
Lim’s shame campaign generated much publicity, and many questioned the legality and humaneness of singling out unconvicted suspects. Former Senator Rene A. Saguisag, a member of Movement for Brotherhood, Integrity and Nationalism, Inc. (MABINI), issued a public statement condemning Lim’s policy: "The shame campaign violated presumption of innocence because it transgresses due process…" In January 2000, the 14th Division of the Court of Appeals ruled the policy as "invalid and unconstitutional."[2]
In January 2005, Metro Manila Development Authority Chair Bayani Fernando announced a "wet rags shame campaign" to target commuters who wait for rides in the middle of the streets. The MMDA traffic enforcers planned to punish jaywalkers by driving by in service vehicles and splashing them with wet rags attached to poles. Sound trucks were to drive ahead and warn pedestrians of their approach; those who refused to comply with traffic regulations were to have wet rags dropped on their heads.
Sen. Richard Gordon disagreed with the shame tactic, saying such a way of disciplining pedestrians is a "return to Grade One." He added that the campaign might work for a time but would end up being futile. Rep. Vincent Crisologo of Ilocos Sur, a known critic of Fernando, said the MMDA chief was resorting to martial law tactics. Rep. Rozzano Rufino Biazon of Muntinlupa City, criticized the plan: "It only shows that the MMDA looks at people as animals who should be herded like cattle instead of using reason to make them follow the law… it is an admission that its personnel assigned to the thoroughfares are not doing their job."
Chairman Fernando, unfazed by criticisms, proceeded with the campaign.[3]
In 2005, Tony Kwok, Hong Kong’s former corruption chief, suggested that the Philippine government should carry out a shame campaign to eliminate political corruption. A consultant of the Philippines’ Office of the Ombudsman, Kwok said, "This is what you need, a shame campaign. You have to let the politicians know that corruption is a high-risk crime." Kwok cited Hong Kong’s use of TV advertisements to discourage governmental misconduct. He added, "The best way is through enforcement and education."[4] | https://www.wikidoc.org/index.php/Shame | |
533cbc0d5fb98eaea1794087575927eb49592af0 | wikidoc | Tibia | Tibia
The tibia is the larger of the two bones in the leg below the knee in vertebrates.
# In humans
The tibia or shin bone, in human anatomy, is found medial (towards the middle) and anterior (towards the front) to the other such bone, the fibula. It is the second-longest bone in the human body, the largest being the femur. The tibia articulates with the femur and patella superiorly, the fibula laterally and with the ankle inferiorly.
## Gender differences
In the male, its direction is vertical, and parallel with the bone of the opposite side, but in the female it has a slightly oblique direction downward and lateralward, to compensate for the greater obliquity of the femur.
## Structure
It is prismoid in form, expanded above, where it enters into the knee-joint, contracted in the lower third, and again enlarged but to a lesser extent below.
The tibia is connected to the fibula by an interosseous membrane, forming a type of joint called a syndesmoses.
## Blood supply
The tibia derives its arterial blood supply from two sources:
- the nutrient artery (main source)
- periosteal vessels derived from the anterior tibial artery
# Additional images
- Lower extremity
- Knee diagram
- Bones of the right leg. Anterior surface.
- Bones of the right leg. Posterior surface.
- Right knee-joint. Posterior view.
- Right knee-joint, from the front, showing interior ligaments.
- Left knee-joint from behind, showing interior ligaments.
- Sagittal section of right knee-joint.
- Capsule of right knee-joint (distended). Lateral aspect.
- Capsule of right knee-joint (distended). Posterior aspect.
- Capsule of left talocrura articulation (distended). Lateral aspect.
- Coronal section through right talocrural and talocalcaneal joints.
- Oblique section of left intertarsal and tarsometatarsal articulations, showing the synovial cavities.
- Cross-section through middle of leg. | Tibia
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The tibia is the larger of the two bones in the leg below the knee in vertebrates.
# In humans
The tibia or shin bone, in human anatomy, is found medial (towards the middle) and anterior (towards the front) to the other such bone, the fibula. It is the second-longest bone in the human body, the largest being the femur. The tibia articulates with the femur and patella superiorly, the fibula laterally and with the ankle inferiorly.
## Gender differences
In the male, its direction is vertical, and parallel with the bone of the opposite side, but in the female it has a slightly oblique direction downward and lateralward, to compensate for the greater obliquity of the femur.
## Structure
It is prismoid in form, expanded above, where it enters into the knee-joint, contracted in the lower third, and again enlarged but to a lesser extent below.
The tibia is connected to the fibula by an interosseous membrane, forming a type of joint called a syndesmoses.
## Blood supply
The tibia derives its arterial blood supply from two sources:[1]
- the nutrient artery (main source)
- periosteal vessels derived from the anterior tibial artery
# Additional images
- Lower extremity
- Knee diagram
- Bones of the right leg. Anterior surface.
- Bones of the right leg. Posterior surface.
- Right knee-joint. Posterior view.
- Right knee-joint, from the front, showing interior ligaments.
- Left knee-joint from behind, showing interior ligaments.
- Sagittal section of right knee-joint.
- Capsule of right knee-joint (distended). Lateral aspect.
- Capsule of right knee-joint (distended). Posterior aspect.
- Capsule of left talocrura articulation (distended). Lateral aspect.
- Coronal section through right talocrural and talocalcaneal joints.
- Oblique section of left intertarsal and tarsometatarsal articulations, showing the synovial cavities.
- Cross-section through middle of leg. | https://www.wikidoc.org/index.php/Shin | |
cb0464b24745faf7739247ccef7f2b39ba4245ba | wikidoc | snRNP | snRNP
snRNPs (pronounced "snurps"), or small nuclear ribonucleoproteins, are particles that combine with pre-mRNA and various proteins to form spliceosomes (a type of large molecular complex). SnRNPs "recognize" the places along a strand of pre-mRNA and are essential in the removal of introns. These molecules are found within the cell's nucleus.
The two essential components of snRNPs are protein molecules and RNA. The RNA found within each snRNP particle is known as small nuclear RNA, or snRNA. These molecules are usually about 150 nucleotides long. The snRNA is bound by a Ribonuclear protein (RNP) to activate its enzymatic activity.
The precise beginnings and ends of introns on the primary transcripts are marked by signals so that they can be recognized by the snRNPs and removed. At least four different kinds of snRNPs cooperate in most splicing. The RNA in these particles is like ribosomal RNA in that it is used directly, and has both an enzymatic and a structural role.
SnRNPs were discovered by Michael R. Lerner and Joan A. Steitz.
# Biogenesis
Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleus and cytoplasm.
## Synthesis and export of RNA in the nucleus
The RNA polymerase II transcripts U1, U2, U4, U5 and the less abundant U11, U12 and U4atac (snRNAs) acquire a m7G-cap which serves as export signal. Nuclear export is mediated by CRM1.
## Synthesis and storage of Sm proteins in the cytoplasm
The Sm proteins are synthesized in the cytoplasm by ribosomes translating Sm messenger RNA, just like any other protein. These are stored in the cytoplasm in the form of three partially assembled rings complexes all associated with the pICln protein. They are a 6S pentamer complex of SmD1,SmD2, SmF, SmE and SmG with pICln, a 2-4S complex of B, possibly with D3 and pICln and the 20S methylosome, which is a large complex of SmD3, SmB, SmD1, pICln and the arginine methyltransferase-5 (PRMT5) protein. SmD3, SmB and SmD1 undergo post-translational modification in the methylosome. These three Sm proteins have repeated arginine-glycine motifs in the C-terminal ends of SmD1, SmD3 and SmB, and the arginine side chains are symmetrically dimethylated to ω-NG, NG'-dimethyl-arginine. It has been suggested that pICln, which occurs in all three precursor complexes but is absent in the mature snRNPs, acts as a specialized chaperone, preventing premature assembly of Sm proteins.
## Assembly of core snRNPs in the SMN complex
The snRNAs (U1, U2, U4, U5, and the less abundant U11, U12 and U4atac) quickly interact with the SMN (Survival of Motor Neurons) protein and other proteins (Gemins 2-8) forming the large SMN complex. It is here that the snRNA binds to the SmD1-SmD2-SmF-SmE-SmG pentamer, followed by addition of the SmD3-SmB dimer to complete the Sm ring around the so-called Sm site of the snRNA. This Sm site is a conserved sequence of nucleotides in these snRNAs, typically AUUUGUGG (where A, U and G represent the nucleosides adenosine, uridine and guanosine respectively). After assembly of the Sm ring around the snRNA, the 5' terminal nucleoside (already modified to a 7-methylguanosine cap) is hyper-methylated to 2,2,7-trimethylguanosine and the other (3') end of the snRNA is trimmed. This modification, and the presence of a complete Sm ring, is recognized by the snurportin 1 protein.
## Final assembly of the snRNPs in the nucleus
The completed core snRNP-snurportin 1 complex is transported into the nucleus via the protein importin β. Inside the nucleus, the core snRNPs appear in the Cajal bodies, where final assembly of the snRNPs take place. This consists of additional proteins and other modifications specific to the particular snRNP (U1, U2, U4, U5). The biogenesis of the U6 snRNP occurs in the nucleus although large amounts of free U6 are found in the cytoplasm. The LSm ring may assemble first, and then associate with the U6 snRNA.
## Disassembly of snRNPs
The snRNPs are very long-lived, but are assumed to be eventually disassembled and degraded. Nothing is known about this process.
## Defects in snRNP biogenesis as a cause of Spinal muscular atrophy
Defects in the SMN gene are associated with premature death of spinal motor neurons, and results in Spinal muscular atrophy (SMA). This genetic disease is manifested over a wide range of severity. The most severe form results in paralysis, is usually fatal by age 2, and is the most common genetic cause of infant death.
# Notes
- ↑ Lerner MR, Steitz, JA, "Antibodies to Small Nuclear RNAs Complexed with Proteins are Produced by Patients with Systemic Lupus Erythematosus", PNAS Nov. 1, 1979, v. 76, no. 11, pp. 5495-5499. PMID 316537
- ↑ Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA, "Are snRNPs involved in splicing?", Nature Jan. 10, 1980, v. 283, no. 5743, pp. 220-224. PMID 7350545
- ↑ T. Kiss, "Biogenesis of small nuclear RNPs". Journal of Cell Science (2004) 117:5949-5951. PMID 15564372
- ↑ G. Meister, C. Eggert, D. Buhler, H. Brahms, C. Kambach, U. Fischer, "Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln". Current Biology (2001) 11: 1990-1994. PMID 11747828
- ↑ S. Paushkin, A. K. Gubitz, S. Massenet, G. Dreyfuss, "The SMN complex, an assemblyosome of ribonucleoproteins". Current Opinion in Cell Biology (2002) 14: 305-312. doi:10.1016/S0955-0674(02)00332-0 PMID 12067652
- ↑ J. Yong, L. Wan, G. Dreyfuss, "Why do cells need an assembly machine for RNA-protein complexes?". Trends in Cell Biology (2004) 14:226-232. doi:10.1016/j.tcb.2004.03.010 PMID 15130578
- ↑ P. Selenko, R. Sprangers, G. Stier, D. Buhler, U. Fischer, M. Sattler, "SMN Tudor domain structure and its interaction with the Sm proteins". Nature Structural Biology (2001) 8:27-31. doi:10.1038/83014 PMID 11135666 | snRNP
snRNPs (pronounced "snurps"), or small nuclear ribonucleoproteins, are particles that combine with pre-mRNA and various proteins to form spliceosomes (a type of large molecular complex). SnRNPs "recognize" the places along a strand of pre-mRNA and are essential in the removal of introns. These molecules are found within the cell's nucleus.
The two essential components of snRNPs are protein molecules and RNA. The RNA found within each snRNP particle is known as small nuclear RNA, or snRNA. These molecules are usually about 150 nucleotides long. The snRNA is bound by a Ribonuclear protein (RNP) to activate its enzymatic activity.
The precise beginnings and ends of introns on the primary transcripts are marked by signals so that they can be recognized by the snRNPs and removed. At least four different kinds of snRNPs cooperate in most splicing. The RNA in these particles is like ribosomal RNA in that it is used directly, and has both an enzymatic and a structural role.
SnRNPs were discovered by Michael R. Lerner and Joan A. Steitz.[1][2]
# Biogenesis
Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleus and cytoplasm.[3]
## Synthesis and export of RNA in the nucleus
The RNA polymerase II transcripts U1, U2, U4, U5 and the less abundant U11, U12 and U4atac (snRNAs) acquire a m7G-cap which serves as export signal. Nuclear export is mediated by CRM1.
## Synthesis and storage of Sm proteins in the cytoplasm
The Sm proteins are synthesized in the cytoplasm by ribosomes translating Sm messenger RNA, just like any other protein. These are stored in the cytoplasm in the form of three partially assembled rings complexes all associated with the pICln protein. They are a 6S pentamer complex of SmD1,SmD2, SmF, SmE and SmG with pICln, a 2-4S complex of B, possibly with D3 and pICln and the 20S methylosome, which is a large complex of SmD3, SmB, SmD1, pICln and the arginine methyltransferase-5 (PRMT5) protein. SmD3, SmB and SmD1 undergo post-translational modification in the methylosome.[4] These three Sm proteins have repeated arginine-glycine motifs in the C-terminal ends of SmD1, SmD3 and SmB, and the arginine side chains are symmetrically dimethylated to ω-NG, NG'-dimethyl-arginine. It has been suggested that pICln, which occurs in all three precursor complexes but is absent in the mature snRNPs, acts as a specialized chaperone, preventing premature assembly of Sm proteins.
## Assembly of core snRNPs in the SMN complex
The snRNAs (U1, U2, U4, U5, and the less abundant U11, U12 and U4atac) quickly interact with the SMN (Survival of Motor Neurons) protein and other proteins (Gemins 2-8) forming the large SMN complex.[5][6] It is here that the snRNA binds to the SmD1-SmD2-SmF-SmE-SmG pentamer, followed by addition of the SmD3-SmB dimer to complete the Sm ring around the so-called Sm site of the snRNA. This Sm site is a conserved sequence of nucleotides in these snRNAs, typically AUUUGUGG (where A, U and G represent the nucleosides adenosine, uridine and guanosine respectively). After assembly of the Sm ring around the snRNA, the 5' terminal nucleoside (already modified to a 7-methylguanosine cap) is hyper-methylated to 2,2,7-trimethylguanosine and the other (3') end of the snRNA is trimmed. This modification, and the presence of a complete Sm ring, is recognized by the snurportin 1 protein.
## Final assembly of the snRNPs in the nucleus
The completed core snRNP-snurportin 1 complex is transported into the nucleus via the protein importin β. Inside the nucleus, the core snRNPs appear in the Cajal bodies, where final assembly of the snRNPs take place. This consists of additional proteins and other modifications specific to the particular snRNP (U1, U2, U4, U5). The biogenesis of the U6 snRNP occurs in the nucleus although large amounts of free U6 are found in the cytoplasm. The LSm ring may assemble first, and then associate with the U6 snRNA.
## Disassembly of snRNPs
The snRNPs are very long-lived, but are assumed to be eventually disassembled and degraded. Nothing is known about this process.
## Defects in snRNP biogenesis as a cause of Spinal muscular atrophy
Defects in the SMN gene are associated with premature death of spinal motor neurons, and results in Spinal muscular atrophy (SMA).[7] This genetic disease is manifested over a wide range of severity. The most severe form results in paralysis, is usually fatal by age 2, and is the most common genetic cause of infant death.
# Notes
- ↑ Lerner MR, Steitz, JA, "Antibodies to Small Nuclear RNAs Complexed with Proteins are Produced by Patients with Systemic Lupus Erythematosus", PNAS Nov. 1, 1979, v. 76, no. 11, pp. 5495-5499. PMID 316537
- ↑ Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA, "Are snRNPs involved in splicing?", Nature Jan. 10, 1980, v. 283, no. 5743, pp. 220-224. PMID 7350545
- ↑ T. Kiss, "Biogenesis of small nuclear RNPs". Journal of Cell Science (2004) 117:5949-5951. PMID 15564372
- ↑ G. Meister, C. Eggert, D. Buhler, H. Brahms, C. Kambach, U. Fischer, "Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln". Current Biology (2001) 11: 1990-1994. PMID 11747828
- ↑ S. Paushkin, A. K. Gubitz, S. Massenet, G. Dreyfuss, "The SMN complex, an assemblyosome of ribonucleoproteins". Current Opinion in Cell Biology (2002) 14: 305-312. doi:10.1016/S0955-0674(02)00332-0 PMID 12067652
- ↑ J. Yong, L. Wan, G. Dreyfuss, "Why do cells need an assembly machine for RNA-protein complexes?". Trends in Cell Biology (2004) 14:226-232. doi:10.1016/j.tcb.2004.03.010 PMID 15130578
- ↑ P. Selenko, R. Sprangers, G. Stier, D. Buhler, U. Fischer, M. Sattler, "SMN Tudor domain structure and its interaction with the Sm proteins". Nature Structural Biology (2001) 8:27-31. doi:10.1038/83014 PMID 11135666 | https://www.wikidoc.org/index.php/SnRNP | |
996382d5a5ba61ef8b9b8952e7b1c948e13f808f | wikidoc | Solid | Solid
A solid object is in the states of matter characterized by resistance to deformation and changes of volume.
At the microscopic scale, a solid has these properties :
- The atoms or molecules that comprise the solid are packed closely together.
- These constituent elements have fixed positions in space relative to each other. This accounts for the solid's rigidity. In mineralogy and crystallography, a crystal structure is a unique arrangement of atoms in a crystal. A crystal structure is composed of a unit cell, a set of atoms arranged in a particular way; which is periodically repeated in three dimensions on a lattice. The spacing ,between unit cells in various directions is called its lattice parameters. The symmetry properties of the crystal are embodied in its space group. A crystal's structure and symmetry play a role in determining many of its properties, such as cleavage, electronic band structure, and optical properties.
If sufficient force is applied, either of these properties can be disrupted, causing permanent deformation.
- If sufficient force is applied, either of these properties can be disrupted, causing permanent deformation.
- Because any solid has some thermal energy, its atoms vibrate. However, this movement is very small, and cannot be observed or felt under ordinary conditions.
The branch of physics that deals with solids is called solid-state physics, and is a type of condensed matter physics. Materials science is primarily concerned with properties of solids such as strength and phase transformations. It overlaps strongly with solid-state physics. Solid-state chemistry overlaps both of these fields, but is especially concerned with the synthesis of novel materials.
The lightest known solid is man-made and is called aerogel. The lightest aerogel produced has a density of 1.9 mg/cm³ or 1.9 kg/m³ (1/530 as dense as water).
af:Vastestof
ar:صلب
bs:Čvrsto stanje tvari
bg:Твърдо тяло
ca:Sòlid
cs:Pevná látka
da:Fast form
de:Festkörper
et:Tahkis
el:Στερεό
eo:Solido
eu:Solido
fa:جامد
gl:Sólido
ko:고체
hr:Krutine
id:Padat
is:Storkuhamur
it:Solido
he:מוצק
kn:ಘನ
lv:Cieta viela
jbo:sligu
hu:Szilárd halmazállapot
mk:Цврста агрегатна состојба
ms:Pepejal
nl:Vaste stof
no:Faststoff
nn:Fast stoff
nov:Solide
-m:Solid
qu:Sinchiyasqa
simple:Solid
sk:Pevná látka
sl:Trdnina
fi:Kiinteä olomuoto
sv:Fast form
th:ของแข็ง
uk:Тверде тіло | Solid
Template:Continuum mechanics
A solid object is in the states of matter characterized by resistance to deformation and changes of volume.
At the microscopic scale, a solid has these properties :
- The atoms or molecules that comprise the solid are packed closely together.
- These constituent elements have fixed positions in space relative to each other. This accounts for the solid's rigidity. In mineralogy and crystallography, a crystal structure is a unique arrangement of atoms in a crystal. A crystal structure is composed of a unit cell, a set of atoms arranged in a particular way; which is periodically repeated in three dimensions on a lattice. The spacing ,between unit cells in various directions is called its lattice parameters. The symmetry properties of the crystal are embodied in its space group. A crystal's structure and symmetry play a role in determining many of its properties, such as cleavage, electronic band structure, and optical properties.
If sufficient force is applied, either of these properties can be disrupted, causing permanent deformation.
- If sufficient force is applied, either of these properties can be disrupted, causing permanent deformation.
- Because any solid has some thermal energy, its atoms vibrate. However, this movement is very small, and cannot be observed or felt under ordinary conditions.
The branch of physics that deals with solids is called solid-state physics, and is a type of condensed matter physics. Materials science is primarily concerned with properties of solids such as strength and phase transformations. It overlaps strongly with solid-state physics. Solid-state chemistry overlaps both of these fields, but is especially concerned with the synthesis of novel materials.
The lightest known solid is man-made and is called aerogel. The lightest aerogel produced has a density of 1.9 mg/cm³ or 1.9 kg/m³ (1/530 as dense as water).
Template:State of matter
af:Vastestof
ar:صلب
bs:Čvrsto stanje tvari
bg:Твърдо тяло
ca:Sòlid
cs:Pevná látka
da:Fast form
de:Festkörper
et:Tahkis
el:Στερεό
eo:Solido
eu:Solido
fa:جامد
gl:Sólido
ko:고체
hr:Krutine
id:Padat
is:Storkuhamur
it:Solido
he:מוצק
kn:ಘನ
lv:Cieta viela
jbo:sligu
hu:Szilárd halmazállapot
mk:Цврста агрегатна состојба
ms:Pepejal
nl:Vaste stof
no:Faststoff
nn:Fast stoff
nov:Solide
om:Solid
qu:Sinchiyasqa
simple:Solid
sk:Pevná látka
sl:Trdnina
fi:Kiinteä olomuoto
sv:Fast form
th:ของแข็ง
uk:Тверде тіло
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Solid | |
4ef026c1cc5e64e69655566d8702173f88a919fd | wikidoc | Speed | Speed
Speed is the rate of motion, or equivalently the rate of change in position, many times expressed as distance d traveled per unit of time t.
Speed is a scalar quantity with dimensions distance/time; the equivalent vector quantity to speed is known as velocity. Speed is measured in the same physical units of measurement as velocity, but does not contain the element of direction that velocity has. Speed is thus the magnitude component of velocity.
In mathematical notation, it is simply:
Note that "v" equals velocity.
Objects that move horizontally as well as vertically (such as aircraft) distinguish forward speed and climbing speed.
# Units
Units of speed include:
- meters per second, (symbol m/s), the SI derived unit
- centimeters per second, (symbol cm/s)
- kilometers per hour, (symbol km/h)
- miles per hour, (symbol m/h)
- knots (nautical miles per hour, symbol kt)
- Mach, where Mach 1 is the speed of sound; Mach n is n times as fast.
- speed of light in vacuum (symbol c) is one of the natural units
- Other important conversions
Vehicles often have a speedometer to measure the speed.
# Average speed
Speed as a physical property represents primarily instantaneous speed. In real life we often use average speed (denoted |\tilde{v}|), which is rate of total distance (or length) and time interval.
For example, if you go 60 miles in 2 hours, your average speed during that time is 60/2 = 30 miles per hour, but your instantaneous speed may have varied.
In mathematical notation:
Instantaneous speed defined as a function of time on interval gives average speed:
while instant speed defined as a function of distance (or length) on interval gives average speed:
It is often intuitively expected, but incorrect, that going half a distance with speed |v|_{a} and second half with speed |v|_{b}, produces total average speed |\tilde{v}| = \frac{|v|_a + |v|_b}{2}. The correct value is |\tilde{v}| = \frac{2}{\frac{1}{|v|_a} + \frac{1}{|v|_b}} (Note that the first is a proper arithmetic mean while the second is a proper harmonic mean).
Average speed can be derived also from speed distribution function (either in time or on distance):
# Examples of different speeds
Below are some examples of different speed (see also main article Orders of magnitude (speed)):
- Speed of a common snail = 0.001 m/s; 0.0036 km/h; 0.0023 mph.
- A brisk walk = 1.667 m/s; 6 km/h; 3.75 mph.
- Olympic sprinters (average speed over 100 metres) = 10 m/s; 36 km/h; 22.5 mph.
- Speed limit on a French autoroute = 36.111 m/s; 130 km/h; 80 mph.
- Top cruising speed of a Boeing 747-8 = 290.947 m/s; 1047.41 km/h; 650.83 mph; (officially Mach 0.85)
- Official air speed record = 980.278 m/s; 3,529 km/h; 2,188 mph.
- Space shuttle on re-entry = 7,777.778 m/s; 28,000 km/h; 17,500 mph.
- the speed of sound in air (Mach 1) is about 340 m/s, and 1500 m/s in water
- Taipei 101 Observatory Elevator = 1010 m/min ; 16.667 m/s ; 60.6 km/h; 37.6 mph | Speed
Template:Otheruses1
Speed is the rate of motion, or equivalently the rate of change in position, many times expressed as distance d traveled per unit of time t.
Speed is a scalar quantity with dimensions distance/time; the equivalent vector quantity to speed is known as velocity. Speed is measured in the same physical units of measurement as velocity, but does not contain the element of direction that velocity has. Speed is thus the magnitude component of velocity.
In mathematical notation, it is simply:
Note that "v" equals velocity.
Objects that move horizontally as well as vertically (such as aircraft) distinguish forward speed and climbing speed.
# Units
Units of speed include:
- meters per second, (symbol m/s), the SI derived unit
- centimeters per second, (symbol cm/s)
- kilometers per hour, (symbol km/h)
- miles per hour, (symbol m/h)
- knots (nautical miles per hour, symbol kt)
- Mach, where Mach 1 is the speed of sound; Mach n is n times as fast.
- speed of light in vacuum (symbol c) is one of the natural units
- Other important conversions
Vehicles often have a speedometer to measure the speed.
# Average speed
Speed as a physical property represents primarily instantaneous speed. In real life we often use average speed (denoted <math>|\tilde{v}|</math>), which is rate of total distance (or length) and time interval.
For example, if you go 60 miles in 2 hours, your average speed during that time is 60/2 = 30 miles per hour, but your instantaneous speed may have varied.
In mathematical notation:
Instantaneous speed defined as a function of time on interval <math>[t_0, t_1]</math> gives average speed:
while instant speed defined as a function of distance (or length) on interval <math>[l_0, l_1]</math> gives average speed:
It is often intuitively expected, but incorrect, that going half a distance with speed <math>|v|_{a}</math> and second half with speed <math>|v|_{b}</math>, produces total average speed <math>|\tilde{v}| = \frac{|v|_a + |v|_b}{2}</math>. The correct value is <math>|\tilde{v}| = \frac{2}{\frac{1}{|v|_a} + \frac{1}{|v|_b}}</math> (Note that the first is a proper arithmetic mean while the second is a proper harmonic mean).
Average speed can be derived also from speed distribution function (either in time or on distance):
# Examples of different speeds
Below are some examples of different speed (see also main article Orders of magnitude (speed)):
- Speed of a common snail = 0.001 m/s; 0.0036 km/h; 0.0023 mph.
- A brisk walk = 1.667 m/s; 6 km/h; 3.75 mph.
- Olympic sprinters (average speed over 100 metres) = 10 m/s; 36 km/h; 22.5 mph.
- Speed limit on a French autoroute = 36.111 m/s; 130 km/h; 80 mph.
- Top cruising speed of a Boeing 747-8 = 290.947 m/s; 1047.41 km/h; 650.83 mph; (officially Mach 0.85)
- Official air speed record = 980.278 m/s; 3,529 km/h; 2,188 mph.
- Space shuttle on re-entry = 7,777.778 m/s; 28,000 km/h; 17,500 mph.
- the speed of sound in air (Mach 1) is about 340 m/s, and 1500 m/s in water
- Taipei 101 Observatory Elevator = 1010 m/min ; 16.667 m/s ; 60.6 km/h; 37.6 mph | https://www.wikidoc.org/index.php/Speed | |
6d17520235b8eeea7225296cadbffd2bd6221a92 | wikidoc | Sperm | Sperm
# Overview
The term sperm is derived from the word spermos (meaning "seed") and refers to the male reproductive cells. Sperm cells are the smaller gametes involved in fertilization. In these types of sexual reproduction, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell. A uniflagellar sperm cell that is motile is also referred to as spermatozoon, whereas a non-motile sperm cell is referred to as spermatium. Sperm cells cannot divide and have a limited life span, but they can fuse with egg cells during fertilization to form a totipotent zygote with the potential to develop into a new organism.
The spermatozoa of animals are produced through spermatogenesis inside the male gonads (testicles) through meiosis. Sperm cells in algal and many plant gametophytes are produced in male gametangia (antheridia) through mitosis. In flowering plants, sperm nuclei are produced inside pollen.
# Motile sperm cells
Motile sperm cells typically move via flagella and require water in order to swim toward the egg for fertilization. The uniflagellated sperm cells (with one flagellum) produced in most animals are referred to as spermatozoa, and are known to vary in size.
In nematodes, the sperm cells crawl, rather than swim, towards the egg cell.
# Non-motile sperm cells
Non-motile sperm cells called spermatia lack flagella and therefore cannot swim. They are often confused with conidia. Conidia are spores that germinate independently of fertilization, whereas spermatia are gametes that cannot give rise to a new organism by themselves, but instead are required for fertilization. Spermatia are produced in a spermatangium.
Because spermatia cannot swim, they depend on their environment to carry them to the egg cell. Some red algae produce non-motile spermatia that are spread by water currents after their release. The spermatia of rust fungi are covered with a sticky substance. They are produced in flask-shaped structures containing nectar, which attract flies that transfer the spermatia to nearby hyphae for fertilization in a mechanism similar to insect pollination in flowering plants.
# Sperm nuclei
In many land plants, including most gymnosperms and all angiosperms, the male gametophytes (pollen grains) are the primary mode of dispersal, for example via wind or insect pollination, eliminating the need for water to bridge the gap between male and female. Each pollen grain contains a spermatogenous (generative) cell. Once the pollen lands on the stigma of a receptive flower, it germinates and starts growing a pollen tube through the carpel. Before the tube reaches the ovule, the nucleus of the generative cell in the pollen grain divides and gives rise to two sperm nuclei which are then discharged through the tube into the ovule for fertilization.
In some protists, fertilization also involves sperm nuclei, rather than cells, migrating toward the egg cell through a fertilization tube. Oomycetes form sperm nuclei in a syncytical antheridium surrounding the egg cells. The sperm nuclei reach the eggs through fertilization tubes, similar to the pollen tube mechanism in plants. | Sperm
# Overview
The term sperm is derived from the word spermos (meaning "seed") and refers to the male reproductive cells. Sperm cells are the smaller gametes involved in fertilization. In these types of sexual reproduction, there is a marked difference in the size of the gametes with the smaller one being termed the "male" or sperm cell. A uniflagellar sperm cell that is motile is also referred to as spermatozoon, whereas a non-motile sperm cell is referred to as spermatium. Sperm cells cannot divide and have a limited life span, but they can fuse with egg cells during fertilization to form a totipotent zygote with the potential to develop into a new organism.
The spermatozoa of animals are produced through spermatogenesis inside the male gonads (testicles) through meiosis. Sperm cells in algal and many plant gametophytes are produced in male gametangia (antheridia) through mitosis. In flowering plants, sperm nuclei are produced inside pollen.
# Motile sperm cells
Motile sperm cells typically move via flagella and require water in order to swim toward the egg for fertilization. The uniflagellated sperm cells (with one flagellum) produced in most animals are referred to as spermatozoa, and are known to vary in size.
In nematodes, the sperm cells crawl, rather than swim, towards the egg cell.
# Non-motile sperm cells
Non-motile sperm cells called spermatia lack flagella and therefore cannot swim. They are often confused with conidia. Conidia are spores that germinate independently of fertilization, whereas spermatia are gametes that cannot give rise to a new organism by themselves, but instead are required for fertilization. Spermatia are produced in a spermatangium.
Because spermatia cannot swim, they depend on their environment to carry them to the egg cell. Some red algae produce non-motile spermatia that are spread by water currents after their release. The spermatia of rust fungi are covered with a sticky substance. They are produced in flask-shaped structures containing nectar, which attract flies that transfer the spermatia to nearby hyphae for fertilization in a mechanism similar to insect pollination in flowering plants.
# Sperm nuclei
In many land plants, including most gymnosperms and all angiosperms, the male gametophytes (pollen grains) are the primary mode of dispersal, for example via wind or insect pollination, eliminating the need for water to bridge the gap between male and female. Each pollen grain contains a spermatogenous (generative) cell. Once the pollen lands on the stigma of a receptive flower, it germinates and starts growing a pollen tube through the carpel. Before the tube reaches the ovule, the nucleus of the generative cell in the pollen grain divides and gives rise to two sperm nuclei which are then discharged through the tube into the ovule for fertilization.
In some protists, fertilization also involves sperm nuclei, rather than cells, migrating toward the egg cell through a fertilization tube. Oomycetes form sperm nuclei in a syncytical antheridium surrounding the egg cells. The sperm nuclei reach the eggs through fertilization tubes, similar to the pollen tube mechanism in plants. | https://www.wikidoc.org/index.php/Sperm | |
29d8fdfb6d0e20e2ffab1f6bffc9b25ceb0c9bcf | wikidoc | Spore | Spore
# Overview
In biology, a spore is a reproductive structure that is adapted for dispersion and surviving for extended periods of time in unfavorable conditions. Spores form part of the life cycles of many plants, algae, fungi and some protozoans.
Spores are usually haploid and unicellular and are produced by meiosis in the sporophyte. Once conditions are favorable, the spore can develop into a new organism using mitotic division, producing a multicellular gametophyte, which eventually go on to produce gametes. Two gametes fuse to create a new sporophyte. This cycle is known as alternation of generations, but a better term is "biological life cycle", as there may be more than one phase and so it cannot be an alternation. Haploid spores produced by mitosis (known as mitospores) are used by many fungi for asexual reproduction.
Spores are the units of asexual reproduction as a single spore develops into a new organism. By contrast, gametes are the units of sexual reproduction as two gametes need to fuse to create a new organism.
The term spore may also refer to the dormant stage of some bacteria or archaea; however these are more correctly known as endospores and are not truly spores in the sense discussed in this article. The term can also be loosely applied to some animal resting stages. Fungi that produce spores are known as sporogenous, and those that do not are asporogenous.
The term derives from the ancient Greek word σπορα, meaning seed.
# Classification
Spores can be classified in several ways.
## By function
Diaspores are dispersal units of fungi, mosses, ferns, fern allies, and some other plants. In fungi, chlamydospores are thick-walled resting spores, and zygospores are thick-walled resting spores (hypnozygotes) of zygomycetous fungi which are produced by sexual gametocystogamy and can give rise to a conidiophore ("zygosporangium") with asexual conidiospores.
## By spore-producing structure
In fungi and fungus-like organisms, spores are often classified by the structure in which meiosis and spore production takes place, such as a telium, ascus, basidium, or oogonium, which produce teliospore, ascospores, basidiospores, and oospores, respectively. Since fungi are often classified according to their spore-producing structures, these spores are often characteristic of a particular taxon of the fungi, such as Ascomycota or Basidiomycota.
## By origin during life cycle
Meiospores are the product of meiosis (the critical cytogenetic stage of sexual reproduction), meaning that they are haploid, and give rise to a haploid daughter cell(s) or a haploid individual. An example is the parent of gametophytes of the higher vascular plants (angiosperms and gymnosperms)—the microspores (give rise to pollen) and megaspores (or macrospores) (give rise to ovules) found in flowers and cones; these plants accomplish dispersal by means of seeds.
A mitospore (conidium, conidiospore) is an asexually produced propagule, the result of mitosis. Most fungi produce mitospores. Mitosporic fungi are also known as anamophic fungi (compare teleomorph or deuteromycetes).
## By motility
Spores can be differentiated by whether they can move or not. Zoospore can move by means of one or more flagella, and can be found in some algae and fungi. Aplanospore cannot move, but may potentially grow flagella. Autospore cannot move and cannot develop flagella. Ballistospore are actively discharged from the body of a fungal fruit (such as a mushroom). Statismospore are not actively discharged from the fungal fruit body, similarly to a puffball.
# Parlance
In common parlance, the difference between "spore" and "gamete" (both together called gonites) is that a spore will germinate and develop into a sporeling, while a gamete needs to combine with another gamete before developing further. However, the terms are somewhat interchangeable when referring to gametes.
A chief difference between spores and seeds as dispersal units is that spores have very little stored food resources compared with seeds, and thus require more favorable conditions in order to successfully germinate. Seeds, therefore, are more resistant to harsh conditions and require less energy to start mitosis. Spores are usually produced in large numbers to increase the chance of a spore surviving.
The endospores of certain bacteria are often incorrectly called spores, as seen in the 2001 anthrax attacks where the media called anthrax endospores "anthrax spores". Unlike eukaryotic spores, endospores are primarily a survival mechanism, not a reproductive method, and a bacterium only produces a single endospore.
# Diaspores
In the case of spore-shedding vascular plants such as ferns, wind distribution of very light spores provides great capacity for dispersal. Also, spores are less subject to animal predation than seeds because they contain almost no food reserve; however they are more subject to fungal and bacterial predation. Their chief advantage is that, of all forms of progeny, spores require the least energy and materials to produce.
Vascular plant spores are always haploid and vascular plants are either homosporous or heterosporous. Plants that are homosporous produce spores of the same size and type. Heterosporous plants, such as spikemosses, quillworts, and some aquatic ferns produce spores of two different sizes: the larger spore in effect functioning as a "female" spore and the smaller functioning as a "male".
Under high magnification, spores can be categorized as either monolete spores or trilete spores. In monolete spores, there is a single line on the spore indicating the axis on which the mother spore was split into four along a vertical axis. In trilete spores, all four spores share a common origin and are in contact with each other, so when they separate each spore shows three lines radiating from a center pole.
# Fungal spores
Parasitic fungal spores may be classified into internal spores, which germinate within the a host, and external spores, also called environmental spores, released by the host to infest other hosts. | Spore
# Overview
In biology, a spore is a reproductive structure that is adapted for dispersion and surviving for extended periods of time in unfavorable conditions. Spores form part of the life cycles of many plants, algae, fungi and some protozoans.[1]
Spores are usually haploid and unicellular and are produced by meiosis in the sporophyte. Once conditions are favorable, the spore can develop into a new organism using mitotic division, producing a multicellular gametophyte, which eventually go on to produce gametes. Two gametes fuse to create a new sporophyte. This cycle is known as alternation of generations, but a better term is "biological life cycle", as there may be more than one phase and so it cannot be an alternation. Haploid spores produced by mitosis (known as mitospores) are used by many fungi for asexual reproduction.
Spores are the units of asexual reproduction as a single spore develops into a new organism. By contrast, gametes are the units of sexual reproduction as two gametes need to fuse to create a new organism.
The term spore may also refer to the dormant stage of some bacteria or archaea; however these are more correctly known as endospores and are not truly spores in the sense discussed in this article. The term can also be loosely applied to some animal resting stages. Fungi that produce spores are known as sporogenous, and those that do not are asporogenous.
The term derives from the ancient Greek word σπορα, meaning seed.
# Classification
Spores can be classified in several ways.
## By function
Diaspores are dispersal units of fungi, mosses, ferns, fern allies, and some other plants. In fungi, chlamydospores are thick-walled resting spores, and zygospores are thick-walled resting spores (hypnozygotes) of zygomycetous fungi which are produced by sexual gametocystogamy and can give rise to a conidiophore ("zygosporangium") with asexual conidiospores.
## By spore-producing structure
In fungi and fungus-like organisms, spores are often classified by the structure in which meiosis and spore production takes place, such as a telium, ascus, basidium, or oogonium, which produce teliospore, ascospores, basidiospores, and oospores, respectively. Since fungi are often classified according to their spore-producing structures, these spores are often characteristic of a particular taxon of the fungi, such as Ascomycota or Basidiomycota.
## By origin during life cycle
Meiospores are the product of meiosis (the critical cytogenetic stage of sexual reproduction), meaning that they are haploid, and give rise to a haploid daughter cell(s) or a haploid individual. An example is the parent of gametophytes of the higher vascular plants (angiosperms and gymnosperms)—the microspores (give rise to pollen) and megaspores (or macrospores) (give rise to ovules) found in flowers and cones; these plants accomplish dispersal by means of seeds.
A mitospore (conidium, conidiospore) is an asexually produced propagule, the result of mitosis. Most fungi produce mitospores. Mitosporic fungi are also known as anamophic fungi (compare teleomorph or deuteromycetes).
## By motility
Spores can be differentiated by whether they can move or not. Zoospore can move by means of one or more flagella, and can be found in some algae and fungi. Aplanospore cannot move, but may potentially grow flagella. Autospore cannot move and cannot develop flagella. Ballistospore are actively discharged from the body of a fungal fruit (such as a mushroom). Statismospore are not actively discharged from the fungal fruit body, similarly to a puffball.
# Parlance
In common parlance, the difference between "spore" and "gamete" (both together called gonites) is that a spore will germinate and develop into a sporeling, while a gamete needs to combine with another gamete before developing further. However, the terms are somewhat interchangeable when referring to gametes.
A chief difference between spores and seeds as dispersal units is that spores have very little stored food resources compared with seeds, and thus require more favorable conditions in order to successfully germinate. Seeds, therefore, are more resistant to harsh conditions and require less energy to start mitosis. Spores are usually produced in large numbers to increase the chance of a spore surviving.
The endospores of certain bacteria are often incorrectly called spores, as seen in the 2001 anthrax attacks where the media called anthrax endospores "anthrax spores". Unlike eukaryotic spores, endospores are primarily a survival mechanism, not a reproductive method, and a bacterium only produces a single endospore.
# Diaspores
In the case of spore-shedding vascular plants such as ferns, wind distribution of very light spores provides great capacity for dispersal. Also, spores are less subject to animal predation than seeds because they contain almost no food reserve; however they are more subject to fungal and bacterial predation. Their chief advantage is that, of all forms of progeny, spores require the least energy and materials to produce.
Vascular plant spores are always haploid and vascular plants are either homosporous or heterosporous. Plants that are homosporous produce spores of the same size and type. Heterosporous plants, such as spikemosses, quillworts, and some aquatic ferns produce spores of two different sizes: the larger spore in effect functioning as a "female" spore and the smaller functioning as a "male".
Under high magnification, spores can be categorized as either monolete spores or trilete spores. In monolete spores, there is a single line on the spore indicating the axis on which the mother spore was split into four along a vertical axis. In trilete spores, all four spores share a common origin and are in contact with each other, so when they separate each spore shows three lines radiating from a center pole.
# Fungal spores
Parasitic fungal spores may be classified into internal spores, which germinate within the a host, and external spores, also called environmental spores, released by the host to infest other hosts. [2] | https://www.wikidoc.org/index.php/Spore | |
a49bcbc64686fd959cc41d3549d026b68f3eb7b9 | wikidoc | Steam | Steam
In physical chemistry, and in engineering, steam refers to vaporized water. It is a pure, completely invisible gas (for mist see below). At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600 times the volume of liquid water. In the atmosphere, the partial pressure of water is much lower than 1 atm, therefore gaseous water can exist at temperatures much lower than 100 C (see water vapor and humidity).
In common speech, steam most often refers to the white mist that condenses above boiling water as the hot vapor ("steam" in the first sense) mixes with the cooler air. This mist is made of tiny droplets of liquid water, not gaseous water, so it is no longer technically steam. In the spout of a steaming kettle, the spot where there is no condensed water vapor, where there appears to be nothing there, is steam.
# Uses
A steam engine uses the expansion of steam in order to drive a piston or turbine to perform mechanical work. In other industrial applications steam is used for energy storage, which is introduced and extracted by heat transfer, usually through pipes. Steam is a capacious reservoir for energy because of water's high heat of vaporization. The ability to return condensed steam as water-liquid to the boiler at high pressure with relatively little expenditure of pumping power is also important. Engineers use an idealised thermodynamic cycle, the Rankine cycle, to model the behaviour of steam engines.
In the U.S., more than 86% of electric power is produced using steam as the working fluid, nearly all by steam turbines. Condensation of steam to water often occurs at the low-pressure end of a steam turbine, since this maximises the energy efficiency, but such wet-steam conditions have to be limited to avoid excessive turbine blade erosion.
When liquid water comes in contact with a very hot substance (such as lava, or molten metal) it can flash into steam very quickly; this is called a steam explosion. Such an explosion was probably responsible for much of the damage in the Chernobyl accident and for many so-called 'foundry accidents'.
Steam's capacity to transfer heat is also used in the home: for cooking vegetables, steam cleaning of fabric and carpets, and heating buildings. In each case, water is heated in a boiler, and the steam carries the energy to a target object. "Steam showers" are actually low-temperature mist-generators, and do not actually use steam.
In electric generation, steam is typically condensed at the end of its expansion cycle, and returned to the boiler for re-use. However in cogeneration, steam is piped into buildings to provide heat energy after its use in the electric generation cycle. The world's biggest steam generation system is Con Edison in New York City which pumps steam into 100,000 buildings in Manhattan from seven cogeneration plants. | Steam
In physical chemistry, and in engineering, steam refers to vaporized water. It is a pure, completely invisible gas (for mist see below). At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600 times the volume of liquid water. In the atmosphere, the partial pressure of water is much lower than 1 atm, therefore gaseous water can exist at temperatures much lower than 100 C (see water vapor and humidity).
In common speech, steam most often refers to the white mist that condenses above boiling water as the hot vapor ("steam" in the first sense) mixes with the cooler air. This mist is made of tiny droplets of liquid water, not gaseous water, so it is no longer technically steam. In the spout of a steaming kettle, the spot where there is no condensed water vapor, where there appears to be nothing there, is steam.
# Uses
A steam engine uses the expansion of steam in order to drive a piston or turbine to perform mechanical work. In other industrial applications steam is used for energy storage, which is introduced and extracted by heat transfer, usually through pipes. Steam is a capacious reservoir for energy because of water's high heat of vaporization. The ability to return condensed steam as water-liquid to the boiler at high pressure with relatively little expenditure of pumping power is also important. Engineers use an idealised thermodynamic cycle, the Rankine cycle, to model the behaviour of steam engines.
In the U.S., more than 86% of electric power is produced using steam as the working fluid, nearly all by steam turbines. Condensation of steam to water often occurs at the low-pressure end of a steam turbine, since this maximises the energy efficiency, but such wet-steam conditions have to be limited to avoid excessive turbine blade erosion.
When liquid water comes in contact with a very hot substance (such as lava, or molten metal) it can flash into steam very quickly; this is called a steam explosion. Such an explosion was probably responsible for much of the damage in the Chernobyl accident and for many so-called 'foundry accidents'.
Steam's capacity to transfer heat is also used in the home: for cooking vegetables, steam cleaning of fabric and carpets, and heating buildings. In each case, water is heated in a boiler, and the steam carries the energy to a target object. "Steam showers" are actually low-temperature mist-generators, and do not actually use steam.
In electric generation, steam is typically condensed at the end of its expansion cycle, and returned to the boiler for re-use. However in cogeneration, steam is piped into buildings to provide heat energy after its use in the electric generation cycle. The world's biggest steam generation system is Con Edison in New York City which pumps steam into 100,000 buildings in Manhattan from seven cogeneration plants.[1] | https://www.wikidoc.org/index.php/Steam | |
e0e18cb08d662f3f13ae5038ac5f1803385b7fb7 | wikidoc | Sugar | Sugar
# Overview
In non-scientific use, the term sugar refers to sucrose (also called "table sugar" or "saccharose") — a white crystalline solid disaccharide. Humans most commonly use sucrose as their sugar of choice for altering the flavor and properties (such as mouthfeel, preservation, and texture) of beverages and food. Commercially produced table sugar comes either from sugar cane or from sugar beet. Manufacturing and preparing food may involve other sugars, including palm sugar and fructose, generally obtained from corn (maize) or fruit.
In this informal sense, the word "sugar" principally refers to crystalline sugars; but a great many foods exist which principally contain sugar: these generally appear as syrups, or have specific names such as "honey" or "molasses." Many of these comprise mostly sugar; and sugar may dissolve in water to form a syrup.
Scientifically, sugar refers to any monosaccharide or disaccharide. Monosaccharides (also called "simple sugars"), such as glucose, store chemical energy which biological cells convert to other types of energy.
In a list of ingredients, any word that ends with "ose" will likely denote a sugar. Sometimes such words may also refer to any types of carbohydrates soluble in water.
In culinary terms, the foodstuff known as sugar delivers a primary taste sensation of sweetness. Apart from the many forms of sugar and of sugar-containing foodstuffs, alternative non-sugar-based sweeteners exist, and particularly interest people who have problems with their blood sugar level (such as diabetics) and people who wish to limit their calorie-intake, but while enjoying sweet foods to a greater degree. Both natural and synthetic examples exist with no significant carbohydrate (calorie) content, for instance stevia (a herb) and saccharin (produced from naturally occurring but not necessarily naturally edible substances by inducing appropriate chemical reactions).
# Sugar and society
For many years, sugar has been distributed through society and has helped shape the community. One example of this is sugar and its effects with language, such as "give me some sugar" or "you're sweet as sugar." Many more alterations of society have been swayed by Sugar, especially in the southern regions of the earth.
# History
## Early use of sugar-cane in Asia
Sugar-cane, a tropical grass, probably originated in New Guinea. During prehistoric times its culture spread throughout the Pacific Islands and into India. By 200 BC producers in China had begun to grow it too. Westerners learned of sugar cane in the course of military expeditions to India. Nearchos, one of Alexander the Great's commanders, described it as "a reed that gives honey without bees".
Originally, people chewed the cane raw to extract its sweetness. The process of making sugar by evaporating juice from sugar cane developed in India around 500 BC. In South Asia, the Middle East and China, sugar became a staple of cooking and desserts.
Early refining methods involved grinding or pounding the cane in order to extract the juice, and then boiling down the juice or drying it in the sun to yield sugary solids that resembled gravel. The Sanskrit word for "sugar" (sharkara), also means "gravel". Similarly, the Chinese use the term "gravel sugar" (Traditional Chinese: 砂糖) for table sugar.
## Cane sugar outside Asia
During the Muslim Agricultural Revolution, sugar production was adopted from India and then refined and transformed into a large-scale industry by the Arabs, who built the first sugar mills, refineries, factories and plantations. The Arabs and Berbers diffused sugar throughout the Arab Empire and beyond across much of the Old World, including Western Europe after they conquered the Iberian Peninsula in the 8th century AD. Crusaders also brought sugar home with them after their campaigns in the Holy Land, where they encountered caravans carrying "sweet salt". Crusade chronicler William of Tyre, writing in the late 12th century, described sugar as "very necessary for the use and health of mankind".
The 1390s saw the development of a better press, which doubled the juice obtained from the cane. This permitted economic expansion of sugar plantations to Andalucia and to the Algarve. The 1420s saw sugar-production extended to the Canary Islands, Madeira and the Azores.
In August 1492 Christopher Columbus stopped at Gomera in the Canary Islands, for wine and water, intending to stay only four days. He became romantically involved with the Governor of the island, Beatrice de Bobadilla, and stayed a month. When he finally sailed she gave him cuttings of sugar-cane, which became the first to reach the New World.
The Portuguese took sugar to Brazil. Hans Staden, published in 1555, writes that by 1540 Santa Catalina Island had 800 sugar-mills and that the north coast of Brazil, Demarara and Surinam had another 2000. Approximately 3000 small mills built before 1550 in the New World created an unprecedented demand for cast iron gears, levers, axles and other implements. Specialist trades in mold-making and iron-casting developed in Europe due to the expansion of sugar-production. Sugar-mill construction developed technological skills needed for a nascent industrial revolution in the early 17th-century.{
After 1625 the Dutch carried sugar-cane from South America to the Caribbean islands — where it became grown from Barbados to the Virgin Islands. The years 1625 to 1750 saw sugar become worth its weight in gold. Contemporaries often compared the worth of sugar with valuable commodities including musk, pearls, and spices. Prices declined slowly as production became multi-sourced, especially through British colonial policy. Formerly an indulgence of the rich, sugar became increasingly common among the poor. Sugar-production increased in mainland North American colonies, in Cuba, and in Brazil. African slaves became the dominant source of plantation-workers, as they proved resistant to the diseases of malaria and yellow fever. (European indentured servants remained in shorter supply, susceptible to disease and overall forming a less economic investment. European diseases such as smallpox had reduced the numbers of local Native Americans.) But replacement of Native American with African slaves also occurred because of the high death-rates on sugar-plantations. The British West Indies imported almost 4 million slaves, but had only 400,000 Blacks left after slavery ended in the British Empire in 1838.
With the European colonization of the Americas, the Caribbean became the world's largest source of sugar. These islands could supply sugar-cane using slave-labor and produce sugar at prices vastly lower than those of cane-sugar imported from the East. Thus the economies of entire islands such as Guadaloupe and Barbados became based on sugar-production. By 1750 the French colony known as Saint-Domingue (subsequently the independent country of Haiti) became the largest sugar-producer in the world. Jamaica too became a major producer in the 18th century. Sugar-plantations fueled a demand for manpower; between 1701 and 1810 ships brought nearly one million slaves to work in Jamaica and in Barbados.
During the eighteenth century, sugar became enormously popular and the sugar-market went through a series of booms. The heightened demand and production of sugar came about to a large extent due to a great change in the eating habits of many Europeans. For example, they began consuming jams, candy, tea, coffee, cocoa, processed foods, and other sweet victuals in much greater numbers. Reacting to this increasing craze, the islands took advantage of the situation and began producing more sugar. In fact, they produced up to ninety percent of the sugar that the western Europeans consumed. Some islands proved more successful than others when it came to producing the product. And in Barbados and the British Leeward Islands sugar provided 93% and 97% respectively of exports.
Planters later began developing ways to boost production even more. For example, they began using more manure when growing their crops. They also developed more advanced mills and began using better types of sugar-cane. Despite these and other improvements, the price of sugar reached soaring heights, especially during events such as the revolt against the Dutch and the Napoleonic Wars. Sugar remained in high demand, and the islands' planters knew exactly how to take advantage of the situation.
As Europeans established sugar-plantations on the larger Caribbean islands, prices fell, especially in Britain. By the eighteenth century all levels of society had become common consumers of the former luxury product. At first most sugar in Britain went into tea, but later confectionery and chocolates became extremely popular. Many Britons (especially children) also ate jams. Suppliers commonly sold sugar in solid cones and consumers required a sugar nip, a pliers-like tool, to break off pieces.
Sugar-cane quickly exhausts the soil in which it grows, and planters pressed larger islands with fresher soil into production in the nineteenth century. In this century, for example, Cuba rose to become the richest land in the Caribbean (with sugar as its dominant crop) because it formed the only major island land-mass free of mountainous terrain. Instead, nearly three-quarters of its land formed a rolling plain — ideal for planting crops. Cuba also prospered above other islands because Cubans used better methods when harvesting the sugar crops: they adopted modern milling-methods such as water-mills, enclosed furnaces, steam-engines, and vacuum-pans. All these technologies increased productivity.
After the Haïtian Revolution established the independent state of Haiti, sugar production in that country declined and Cuba replaced Saint-Domingue as the world's largest producer.
Long established in Brazil, sugar-production spread to other parts of South America, as well as to newer European colonies in Africa and in the Pacific, where it became especially important in Fiji.
In Colombia, the planting of sugar started very early on, and entrepreneurs imported many African slaves to cultivate the fields. The industrialization of the Colombian industry started in 1901 with the establishment of the first steam-powered sugar mill by Santiago Eder.
## The rise of beet sugar
In 1747 the German chemist Andreas Marggraf identified sucrose in beet-root. This discovery remained a mere curiosity for some time, but eventually Marggraf's student Franz Achard built a sugarbeet-processing factory at Cunern in Silesia, under the patronage of King Frederick William III of Prussia (reigned 1797 - 1840). While never profitable, this plant operated from 1801 until it suffered destruction during the Napoleonic Wars (ca 1802 - 1815).
Napoleon, cut off from Caribbean imports by a British blockade and at any rate not wanting to fund British merchants, banned imports of sugar in 1813. The beet-sugar industry that emerged in consequence grew, and today sugar-beet provides approximately 30% of world sugar production.
While no longer grown by slaves, sugar from developing countries has an on-going association with workers earning minimal wages and living in extreme poverty.
In the developed countries, the sugar industry relies on machinery, with a low requirement for manpower. A large beet-refinery producing around 1,500 tonnes of sugar a day needs a permanent workforce of about 150 for 24-hour production.
## Mechanization
Beginning in the late 18th century, the production of sugar became increasingly mechanized. The steam engine first powered a sugar-mill in Jamaica in 1768, and soon after, steam replaced direct firing as the source of process heat.
In 1813 the British chemist Edward Charles Howard invented a method of refining sugar that involved boiling the cane juice not in an open kettle, but in a closed vessel heated by steam and held under partial vacuum. At reduced pressure, water boils at a lower temperature, and this development both saved fuel and reduced the amount of sugar lost through caramelization. Further gains in fuel-efficiency came from the multiple-effect evaporator, designed by the African-American engineer Norbert Rillieux (perhaps as early as the 1820s, although the first working model dates from 1845). This system consisted of a series of vacuum pans, each held at a lower pressure than the previous one. The vapors from each pan served to heat the next, with minimal heat wasted. Today, many industries use multiple-effect evaporators for evaporating water.
The process of separating sugar from molasses also received mechanical attention: David Weston first applied the centrifuge to this task in Hawaii in 1852.
# Etymology
The English word "sugar" originates from the Arabic and Persian word shakar. It came to English by way of French, Spanish and/or Italian, which derived their word for sugar from the Arabic and Persian shakar (whence the Portuguese word açúcar, the Spanish word azúcar, the Italian word zucchero, the Old French word zuchre and the contemporary French word sucre). (Compare the OED.) The Greek word for "sugar" is zahari, which means "sugar" or "pebble". Note that the English word jaggery (meaning "coarse brown Indian sugar") has similar ultimate etymological origins (presumably in Sanskrit).
# Sugar as food
Originally a luxury, sugar eventually became sufficiently cheap and common to influence standard cuisine. Britain and the Caribbean islands have cuisines where the use of sugar become particularly prominent.
Sugar forms a major element in confectionery and in desserts. Cooks use it as a food preservative as well as for sweetening.
## Concerns of vegetarians and vegans
The sugar-refining industry often uses bone char (calcinated animal bones) for decolorizing. This concerns vegans and vegetarians; about a quarter of the sugar in the U.S. gets processed using bone char as a filter and the rest gets processed with activated carbon. As bone char does not get into the sugar, the relevant authorities consider sugar processed this way as parve/kosher.
Vegetarians and vegans may also object to the impact that the burning of the cane fields (a common part of the harvesting practice) has on insects, rats, snakes, and other life residing in the fields.
The killing of such species parallels the killing of bees in the course of the production of honey, another sweetener that vegans usually avoid.
# Sugar and health
Whereas historically rotting teeth once seemed the most prominent health-hazard from the use of sugar, first the growth in the usage of rum (a sugar-cane derivative) and then concerns about type 2 diabetes and obesity have gradually come into prominence.
## Tooth-decay
Tooth-decay, arguably the most prominent health hazard associated with the use of sugar, can damage teeth in many ways. Bacteria in the mouth metabolize sugar into various acids. When the pH at the surface of the tooth drops below 5.5 (known as the "critical pH"), the acids start dissolving tooth-enamel. This results in decay of the tooth.
## Diabetes
Diabetes, a disease that causes the body to metabolize sugar poorly, occurs when either:
- the body's cells ignore insulin, a chemical that allows the metabolizing of sugar (Type 2 diabetes)
- the body attacks the cells producing the insulin (Type 1 diabetes)
When glucose builds up in the bloodstream, it can cause two problems:
- in the short term, cells become starved for energy because they do not have access to the glucose
- in the long term, frequent glucose build-up can damage many of the body's organs, including the eyes, kidneys, nerves and/or heart
However, while sugars may adversely affect those with diabetes, science has not proven that sugars cause diabetes.
## Obesity
In the United States of America, a scientific/health debate has startedover the causes of a steep rise in obesity in the general population — and one view posits increased consumption of carbohydrates in recent decades as a major factor.
Obesity can result from a number of factors including:
- an increased intake of energy-dense foods — high in fat and sugars but low in vitamins, minerals and other micronutrients; and
- decreased physical activity.
## United Nations nutritional advice
In 2003, four United Nations agencies, (including the World Health Organization (WHO) and the Food and Agriculture Organization (FAO)) commissioned a report compiled by a panel of 30 international experts. The panel stated that the total of free sugars (all monosaccharides and disaccharides added to foods by manufacturers, cooks or consumers, plus sugars naturally present in honey, syrups and fruit juices) should not account for more than 10% of the energy intake of a healthy diet, while carbohydrates in total should represent between 55% and 75% of the energy-intake (table 6, page 56 of the WHO Technical Report Series 916, Diet, Nutrition and the Prevention of Chronic Diseases: see #bm07.1.3 ).
## Sugar producers’ nutritional advice
In contradistinction to the United Nations report, the Sugar Association of the United States of America insists that other evidence indicates that a quarter of human food and drink intake can safely consist of sugar.
## Debate on extrinsic sugar
Argument continues as to the value of extrinsic sugar (sugar added to food) compared to that of intrinsic sugar (sugars - seldom sucrose - naturally present in food). Adding sugar to food particularly enhances taste, but has drawbacks of boosting calories, among other negative effects on health and physiology.
In the United States of America, sugar has become increasingly evident in food products, as more food-manufacturers add sugar or high-fructose corn-syrup to a wide variety of consumables. Candy-bars, soft drinks, chips, snacks, fruit-juice, peanut-butter, soups, ice-cream, jams, jellies, yogurt, and many breads have added sugars. Five Alive, for example, portrayed by its suppliers as "all natural" and featuring pictures of five different types of fruit on its label, comprises only 41% fruit juice, having high-fructose corn-syrup as its prime ingredient.
Many doctors argue that health authorities should classify sugar and high-fructose corn-syrup as food additives.
Some go so far as to call refined sugar a poison.
The anthropologist and dentist Weston A. Price, writing in 1939,
correlated the use of refined sugar (and refined grains) with malnutrition in pregnant women, malformation of the palate and jaw in their children, followed by cramping of teeth in adolescence (leading to crooked teeth and the removal of wisdom teeth molars). Price correlated other ailments and the impaired function of the pituitary or master gland with consumption of refined sugar, as well as rates of infant mortality, subnormal intelligence, delinquency, and incarceration. He also correlated the underdevelopment of the pelvis, which in women would lead to complications (pain, death, etc.) in childbirth.
Virtually all of these symptoms became the norm in modern populations consuming typical amounts of refined sugar and other "modern foods of commerce". Besides the rotting of teeth, interruptible or resumable merely by removing or re-introducing white sugar into a diet, the correlations with consumption of refined sugar may relate less to the consumption of refined sugar itself than to the absence of the consumption of "nourishment", a category in which Price did not include refined sugar.
## Nutrition
Sugar-cane in its natural form provides a rich source of vitamins and minerals, but refined sugar lacks many nutrients.
## Sugar and hyperactivity
Sugar (not only sucrose, but also other varieties such as glucose) may cause some children to become hyperactive — giving rise to the terms "sugar high", "sugar rush" and "sugar buzz". Recent studies financed by the sugar-industry found that in a party situation all children became very active after only some had consumed sugar, thus demonstrating the lack of a direct link between individual consumption of sugar and individual levels of hyperactivity in that party context, even when the researchers focused on children with a presumed "sugar-sensitivity". If sugar-industry researchers believe sugar does not contribute to hyperactivity, or if parents and teachers believe in the possibility of a sugar-high, their respective biases may cause them to perceive children accordingly after consumption of sweets and sugary beverages through observer-bias. (Note that the experiments did not take place in the context of a control-group following a base diet-level matching the recommendation of the WHO/FAO (stated above) to avoid the impacts of added extrinsic sugars cited above, nor in a controlled setting — and so could not give credible results.)
Some commentators believe that children and adults show the hyperactive effects of sugar equally. On average, Americans eat or drink approximately five pounds of sugar a month.
# Production
Table sugar (sucrose) comes from plant sources. Two important sugar crops predominate: sugarcane (Saccharum spp.) and sugar beets (Beta vulgaris), in which sugar can account for 12% to 20% of the plant's dry weight. Some minor commercial sugar crops include the date palm (Phoenix dactylifera), sorghum (Sorghum vulgare), and the sugar maple (Acer saccharum). In the financial year 2001/2002, worldwide production of sugar amounted to 134.1 million tonnes.
The first production of sugar from sugar-cane took place in India. Alexander the Great's companions reported seeing "honey produced without the intervention of bees" and it remained exotic in Europe until the Arabs started cultivating it in Sicily and Spain. Only after the Crusades did it begin to rival honey as a sweetener in Europe. The Spanish began cultivating sugar-cane in the West Indies in 1506 (and in Cuba in 1523). The Portuguese first cultivated sugar-cane in Brazil in 1532.
Most cane-sugar comes from countries with warm climates, such as Brazil, India, China, Thailand, Mexico and Australia, the five top sugar producing countries in the world. Brazil overshadows most countries with roughly 30 million tonnes of cane sugar produced in 2006, while India produced 21 million, China 11 million, and Thailand and Mexico at roughly 5 million. Viewed by region, Asia is the world-leader in cane-sugar production with large contributions from China, India and Thailand and other countries combining to account for 40% of global production in 2006. South America comes in second place with 32% of global production, Africa and Central America both at 8% and Australia at 5%. The United States, the Caribbean and Europe make up the remainder with roughly 3% each.
Beet-sugar comes from regions with cooler climates: northwest and eastern Europe, northern Japan, plus some areas in the United States (including California). In the northern hemisphere, the beet-growing season ends with the start of harvesting around September. Harvesting and processing continues until March in some cases. The availability of processing-plant capacity, and the weather both influence the duration of harvesting and processing - the industry can lay up harvested beet until processed, but frost-damaged beet becomes effectively unprocessable.
The European Union (EU) has become the world's second-largest sugar exporter. The Common Agricultural Policy of the EU sets maximum quotas for members' production to match supply and demand, and a price. Europe exports excess production quota (approximately 5 million tonnes in 2003). Part of this, "quota" sugar, gets subsidised from industry levies, the remainder (approximately half) sells as "C quota" sugar at market prices without subsidy. These subsidies and a high import tariff make it difficult for other countries to export to the EU states, or to compete with the Europeans on world markets.
The United States sets high sugar prices to support its producers, with the effect that many former consumers of sugar have switched to corn syrup (beverage-manufacturers) or moved out of the country (candy-makers).
The cheap prices of glucose syrups produced from wheat and corn (maize) threaten the traditional sugar market. In combination with artificial sweeteners, drink manufacturers can produce very low-cost products.
## Cane
Since the 6th century BC cane-sugar producers have crushed the harvested vegetable material from sugar-cane in order to collect and filter the juice. They then treat the liquid (often with lime (calcium oxide)) to remove impurities and then neutralize it. Boiling the juice then allows the sediment to settle to the bottom for dredging out, while the scum rises to the surface for skimming off. In cooling, the liquid crystallizes, usually in the process of stirring, to produce sugar crystals. Centrifuges usually remove the uncrystallized syrup. The producers can then either sell the resultant sugar, as is, for use; or process it further to produce lighter grades. This processing may take place in another factory in another country.
## Beet
Beet-sugar producers slice the washed beets, then extract the sugar with hot water in a "diffuser". An alkaline solution ("milk of lime" and carbon dioxide from the lime kiln) then serves to precipitate impurities (see carbonatation). After filtration, evaporation concentrates the juice to a content of about 70% solids, and controlled crystallisation extracts the sugar. A centrifuge removes the sugar crystals from the liquid, which gets recycled in the crystalliser stages. When economic constraints prevent the removal of more sugar, the manufacturer discards the remaining liquid, now known as molasses.
Sieving the resultant white sugar produces different grades for selling.
## Cane versus beet
Little perceptible difference exists between sugar produced from beet and that from cane. Tests can distinguish the two, and some tests aim to detect fraudulent abuse of EU subsidies or to aid in the detection of adulterated fruit-juice.
The production of sugar results in residues which differ substantially depending on the raw materials used and on the place of production. While cooks often use cane molasses in food, humans find molasses from sugar beet unpalatable, and it therefore ends up mostly as industrial fermentation feedstock, or as animal-feed. Once dried, either type of molasses can serve as fuel for burning.
## Culinary sugars
So-called raw sugars comprise yellow to brown sugars made by clarifying the source syrup by boiling and drying with heat, until it becomes a crystalline solid, with minimal chemical processing. Raw beet sugars result from the processing of sugar-beet juice, but only as intermediates en route to white sugar. Types of raw sugar include demerara, muscovado, and turbinado. Mauritius and Malawi export significant quantities of such specialty sugars. Manufacturers sometimes prepare raw sugar as loaves rather than as a crystalline powder, by pouring sugar and molasses together into molds and allowing the mixture to dry. This results in sugar-cakes or loaves, called jaggery or gur in India, pingbian tang in China, and panela, panocha, pile, piloncillo and pão-de-açúcar in various parts of Latin America. In South America, truly raw sugar, unheated and made from sugar-cane grown on farms, does not have a large market-share.
Mill white sugar, also called plantation white, crystal sugar, or superior sugar, consists of raw sugar where the production process does not remove colored impurities, but rather bleaches them white by exposure to sulfur dioxide. Though the most common form of sugar in sugarcane-growing areas, this product does not store or ship well; after a few weeks, its impurities tend to promote discoloration and clumping.
Blanco directo, a white sugar common in India and other south Asian countries, comes from precipitating many impurities out of the cane juice by using phosphatation — a treatment with phosphoric acid and calcium hydroxide similar to the carbonatation technique used in beet-sugar refining. In terms of sucrose purity, blanco directo is more pure than mill white, but less pure than white refined sugar.
White refined sugar has become the most common form of sugar in North America as well as in Europe. Refined sugar can be made by dissolving raw sugar and purifying it with a phosphoric acid method similar to that used for blanco directo, a carbonatation process involving calcium hydroxide and carbon dioxide, or by various filtration strategies. It is then further purified by filtration through a bed of activated carbon or bone char depending on where the processing takes place. Beet sugar refineries produce refined white sugar directly without an intermediate raw stage. White refined sugar is typically sold as granulated sugar, which has been dried to prevent clumping.
Granulated sugar comes in various crystal sizes — for home and industrial use — depending on the application:
- Coarse-grained sugars, such as sanding sugar (nibbed sugar or sugar nibs) find favor for decorating cookies/biscuits and other desserts.
- Normal granulated sugars for table use: typically they have a grain size about 0.5 mm across
- Finer grades result from selectively sieving the granulated sugar
caster (or castor) (0.35 mm), commonly used in baking
superfine sugar, also called baker's sugar, berry sugar, or bar sugar — favored for sweetening drinks or for preparing meringue
- caster (or castor) (0.35 mm), commonly used in baking
- superfine sugar, also called baker's sugar, berry sugar, or bar sugar — favored for sweetening drinks or for preparing meringue
- Finest grades
Powdered sugar, 10X sugar, confectioner's sugar (0.060 mm), or icing sugar (0.024 mm), produced by grinding sugar to a fine powder. The manufacturer may add a small amount of anti-caking agent to prevent clumping — either cornstarch (1% to 3%) or tri-calcium phosphate. File:Sugarcubes.jpgSugar-cubes close-up.
- Powdered sugar, 10X sugar, confectioner's sugar (0.060 mm), or icing sugar (0.024 mm), produced by grinding sugar to a fine powder. The manufacturer may add a small amount of anti-caking agent to prevent clumping — either cornstarch (1% to 3%) or tri-calcium phosphate. File:Sugarcubes.jpgSugar-cubes close-up.
Retailers also sell sugar cubes or lumps for convenient consumption of a standardised amount. Suppliers of sugar-cubes make them by mixing sugar crystals with sugar syrup. Jakub Kryštof Rad invented sugar-cubes in 1841.
Brown sugars come from the late stages of sugar refining, when sugar forms fine crystals with significant molasses-content, or from coating white refined sugar with a cane molasses syrup. Their color and taste become stronger with increasing molasses-content, as do their moisture-retaining properties. Brown sugars also tend to harden if exposed to the atmosphere, although proper handling can reverse this.
The World Health Organisation and the Food and Agriculture Organization of the United Nations expert report (WHO Technical Report Series 916 Diet, Nutrition and the Prevention of Chronic Diseases) defines free sugars as all monosaccharides and disaccharides added to foods by the manufacturer, cook or consumer, plus sugars naturally present in honey, syrups and fruit-juices. This includes all the sugars referred to above. The term distinguishes these forms from all other culinary sugars added in their natural form with no refining at all.
Natural sugars comprise all completely unrefined sugars: effectively all sugars not defined as free sugars. The WHO Technical Report Series 916 Diet, Nutrition and the Prevention of Chronic Diseases approves only natural sugars as carbohydrates for unrestricted consumption. Natural sugars come in fruit, grains and vegetables in their natural or cooked form.
# Chemistry
Biochemists regard sugars as relatively simple carbohydrates. Sugars include monosaccharides, disaccharides, trisaccharides and the oligosaccharides - containing 1, 2, 3, and 4 or more monosaccharide units respectively. Sugars contain either aldehyde groups (-CHO) or ketone groups (C=O), where there are carbon-oxygen double bonds, making the sugars reactive. Most simple sugars (monosaccharides) conform to (CH2O)n where n is between 3 and 7. A notable exception, deoxyribose, as its name suggests, has a "missing" oxygen atom. All saccharides with more than one ring in their structure result from two or more monosaccharides joined by glycosidic bonds with the resultant loss of a molecule of water (H2O) per bond.
As well as using classifications based on their reactive group, chemists may also subdivide sugars according to the number of carbons they contain. Derivatives of trioses (C3H6O3) are intermediates in glycolysis. Pentoses (5-carbon sugars) include ribose and deoxyribose, which form part of nucleic acids. Ribose also forms a component of several chemicals that have importance in the metabolic process, including NADH and ATP. Hexoses (6-carbon sugars) include glucose, a universal substrate for the production of energy in the form of ATP. Through photosynthesis plants produce glucose, which has the formula C6H12O6, and then convert it for storage as an energy-reserve in the form of other carbohydrates such as starch, or (as in cane and beet) as sucrose (table sugar). The chemical formula for sucrose is C12H22O11.
Many pentoses and hexoses can form ring structures. In these closed-chain forms, the aldehyde or ketone group remains unfree, so many of the reactions typical of these groups cannot occur. Glucose in solution exists mostly in the ring form at equilibrium, with less than 0.1% of the molecules in the open-chain form.
Monosaccharides in a closed-chain form can form glycosidic bonds with other monosaccharides, creating disaccharides (such as sucrose) and polysaccharides (such as starch). Enzymes must hydrolyse or otherwise break these glycosidic bonds before such compounds will be metabolised. After digestion and absorption. the principal monosaccharides present in the blood and internal tissues include glucose, fructose, and galactose.
The prefix "glyco-" indicates the presence of a sugar in an otherwise non-carbohydrate substance. Note for example glycoproteins, proteins which are connected to one or more sugars.
Monosaccharides include fructose, glucose, galactose and mannose. Disaccharides occur most commonly as sucrose (cane or beet sugar - made from one glucose and one fructose), lactose (milk sugar - made from one glucose and one galactose) and maltose (made of two glucoses). These disaccharides have the formula C12H22O11.
Hydrolysis can convert sucrose into a syrup of fructose and glucose, producing invert sugar. This resulting syrup, sweeter than the original sucrose, has uses in making confections because it does not crystallize as easily and thus produces a smoother finished product.
# Measuring sugar
See also International Commission for Uniform Methods of Sugar Analysis
## Dissolved sugar content
Scientists use degrees Brix (symbol °Bx), introduced by Antoine Brix, as units of measurement of the mass ratio of dissolved substance to water in a liquid. A 25 °Bx sucrose solution has 25 grams of sucrose per 100 grams of liquid; or, to put it another way, 25 grams of sucrose sugar and 75 grams of water exist in the 100 grams of solution.
An infrared Brix sensor measures the vibrational frequency of the sugar molecules, giving a Brix degrees measurement. This does not equate to Brix degrees from a density or refractive index measurement because it will specifically measure dissolved sugar concentration instead of all dissolved solids. When using a refractometer, one should report the result as "refractometric dried substance" (RDS). One might speak of a liquid as having 20 °Bx RDS. This refers to a measure of percent by weight of total dried solids and, although not technically the same as Brix degrees determined through an infrared method, renders an accurate measurement of sucrose content, since sucrose in fact forms the majority of dried solids. The advent of in-line infrared Brix measurement sensors has made measuring the amount of dissolved sugar in products economical using a direct measurement.
## Sugar purity
Technicians usually measure the purity of sugar, i.e. the sucrose content, by polarimetry — the measurement of the rotation of plane-polarized light by a solution of sugar.
# Sugar economics
Historically one of the most widely-traded commodities in the world, sugar accounts for around 2% of the global dry cargo market. International sugar prices show great volatility, ranging from around 3 to over 60 cents per pound in the past 50 years. Of the world's 180-odd countries, around 100 produce sugar from beet or cane, a few more refine raw sugar to produce white sugar, and all countries consume sugar. Consumption of sugar ranges from around 3 kilograms per person per annum in Ethiopia to around 40 kg/person/yr in Belgium. Consumption per capita rises with income per capita until it reaches a plateau of around 35kg per person per year in middle-income countries.
Many countries subsidize sugar-production heavily. The European Union, the United States, Japan and many developing countries subsidize domestic production and maintain high tariffs on imports. Sugar prices in these countries have often exceeded prices on the international market by up to three times; today, with world market sugar futures prices currently strong, such prices typically exceed world prices by two times.
Within international trade bodies, especially in the World Trade Organization, the "G20" countries led by Brazil have long argued that because these sugar markets essentially exclude cane-sugar imports, the G20 sugar-producers receive lower prices than they would under free trade. While both the European Union and United States maintain trade agreements whereby certain developing and less-developed countries (LDCs) can sell certain quantities of sugar into their markets, free of the usual import tariffs, countries outside these preferred trade régimes have complained that these arrangements violate the "most favoured nation" principle of international trade.
In 2004, the WTO sided with a group of cane-sugar exporting nations (led by Brazil and Australia) and ruled the EU sugar-régime and the accompanying ACP-EU Sugar Protocol (whereby a group of African, Caribbean, and Pacific countries receive preferential access to the European sugar market) illegal. In response to this and to other rulings of the WTO, and owing to internal pressures on the EU sugar-régime, the European Commission proposed on 22 June 2005 a radical reform of the EU sugar-régime, cutting prices by 39% and eliminating all EU sugar exports.
The African, Caribbean, Pacific and least developed country sugar-exporters reacted with dismay to the EU sugar proposals,. On 25 November 2005 the Council of the EU agreed to cut EU sugar-prices by 36% as from 2009. It now seems that the U.S. Sugar Program could become the next target for reform. However, some commentators expect heavy lobbying from the U.S. sugar-industry, which donated $2.7 million to House and Senate incumbents in the 2006 election, more than any other group of US food growers. Especially prominent in this group are The Fanjul Brothers, sugar barons who are the single largest individual contributors of soft money to both the Democratic and Republican parties in the political system of the United States of America.
Small quantities of sugar, especially specialty grades of sugar, reach the market as 'fair trade' commodities; the fair-trade system produces and sells these products with the understanding that a larger-than-usual fraction of the revenue will support small farmers in the developing world. However, whilst the Fairtrade Foundation offers a premium of USD 60.00 per tonne to small farmers for sugar branded as "Fairtrade",
government schemes such the U.S. Sugar Program and the ACP Sugar Protocol offer premiums of around USD 400.00 per tonne above world market prices. However, the EU announced on 14 September 2007 that it would denounce the ACP Sugar Protocol with effect from 1 October 2009.
The Sugar Association has launched a campaign to promote sugar over artificial substitutes. The Association now aggressively challenges many common beliefs regarding negative side effects of sugar consumption. The campaign aired a high-profile television-commercial during the 2007 Prime Time Emmy Awards on FOX Television. The Sugar Association uses the trademark tagline "Sugar: sweet by nature." | Sugar
# Overview
Template:Nutritionalvalue
Template:Nutritionalvalue
In non-scientific use, the term sugar refers to sucrose (also called "table sugar" or "saccharose") — a white crystalline solid disaccharide. Humans most commonly use sucrose as their sugar of choice for altering the flavor and properties (such as mouthfeel, preservation, and texture) of beverages and food. Commercially produced table sugar comes either from sugar cane or from sugar beet. Manufacturing and preparing food may involve other sugars, including palm sugar and fructose, generally obtained from corn (maize) or fruit.
In this informal sense, the word "sugar" principally refers to crystalline sugars; but a great many foods exist which principally contain sugar: these generally appear as syrups, or have specific names such as "honey" or "molasses." Many of these comprise mostly sugar; and sugar may dissolve in water to form a syrup.
Scientifically, sugar refers to any monosaccharide or disaccharide. Monosaccharides (also called "simple sugars"), such as glucose, store chemical energy which biological cells convert to other types of energy.
In a list of ingredients, any word that ends with "ose" will likely denote a sugar. Sometimes such words may also refer to any types of carbohydrates soluble in water.
In culinary terms, the foodstuff known as sugar delivers a primary taste sensation of sweetness. Apart from the many forms of sugar and of sugar-containing foodstuffs, alternative non-sugar-based sweeteners exist, and particularly interest people who have problems with their blood sugar level (such as diabetics) and people who wish to limit their calorie-intake, but while enjoying sweet foods to a greater degree. Both natural and synthetic examples exist with no significant carbohydrate (calorie) content, for instance stevia (a herb) and saccharin (produced from naturally occurring but not necessarily naturally edible substances by inducing appropriate chemical reactions).
# Sugar and society
For many years, sugar has been distributed through society and has helped shape the community. One example of this is sugar and its effects with language, such as "give me some sugar" or "you're sweet as sugar." Many more alterations of society have been swayed by Sugar, especially in the southern regions of the earth.
# History
## Early use of sugar-cane in Asia
Sugar-cane, a tropical grass, probably originated in New Guinea. During prehistoric times its culture spread throughout the Pacific Islands and into India. By 200 BC producers in China had begun to grow it too. Westerners learned of sugar cane in the course of military expeditions to India. Nearchos, one of Alexander the Great's commanders, described it as "a reed that gives honey without bees".
Originally, people chewed the cane raw to extract its sweetness. The process of making sugar by evaporating juice from sugar cane developed in India around 500 BC. In South Asia, the Middle East and China, sugar became a staple of cooking and desserts.
Early refining methods involved grinding or pounding the cane in order to extract the juice, and then boiling down the juice or drying it in the sun to yield sugary solids that resembled gravel. The Sanskrit word for "sugar" (sharkara), also means "gravel". Similarly, the Chinese use the term "gravel sugar" (Traditional Chinese: 砂糖) for table sugar.
## Cane sugar outside Asia
During the Muslim Agricultural Revolution, sugar production was adopted from India and then refined and transformed into a large-scale industry by the Arabs, who built the first sugar mills, refineries, factories and plantations. The Arabs and Berbers diffused sugar throughout the Arab Empire and beyond across much of the Old World, including Western Europe after they conquered the Iberian Peninsula in the 8th century AD.[1] Crusaders also brought sugar home with them after their campaigns in the Holy Land, where they encountered caravans carrying "sweet salt". Crusade chronicler William of Tyre, writing in the late 12th century, described sugar as "very necessary for the use and health of mankind".
The 1390s saw the development of a better press, which doubled the juice obtained from the cane. This permitted economic expansion of sugar plantations to Andalucia and to the Algarve. The 1420s saw sugar-production extended to the Canary Islands, Madeira and the Azores.
In August 1492 Christopher Columbus stopped at Gomera in the Canary Islands, for wine and water, intending to stay only four days. He became romantically involved with the Governor of the island, Beatrice de Bobadilla, and stayed a month. When he finally sailed she gave him cuttings of sugar-cane, which became the first to reach the New World.
The Portuguese took sugar to Brazil. Hans Staden, published in 1555, writes that by 1540 Santa Catalina Island had 800 sugar-mills and that the north coast of Brazil, Demarara and Surinam had another 2000. Approximately 3000 small mills built before 1550 in the New World created an unprecedented demand for cast iron gears, levers, axles and other implements. Specialist trades in mold-making and iron-casting developed in Europe due to the expansion of sugar-production. Sugar-mill construction developed technological skills needed for a nascent industrial revolution in the early 17th-century.{
After 1625 the Dutch carried sugar-cane from South America to the Caribbean islands — where it became grown from Barbados to the Virgin Islands. The years 1625 to 1750 saw sugar become worth its weight in gold. Contemporaries often compared the worth of sugar with valuable commodities including musk, pearls, and spices. Prices declined slowly as production became multi-sourced, especially through British colonial policy. Formerly an indulgence of the rich, sugar became increasingly common among the poor. Sugar-production increased in mainland North American colonies, in Cuba, and in Brazil. African slaves became the dominant source of plantation-workers, as they proved resistant to the diseases of malaria and yellow fever. (European indentured servants remained in shorter supply, susceptible to disease and overall forming a less economic investment. European diseases such as smallpox had reduced the numbers of local Native Americans.) But replacement of Native American with African slaves also occurred because of the high death-rates on sugar-plantations. The British West Indies imported almost 4 million slaves, but had only 400,000 Blacks left after slavery ended in the British Empire in 1838.
With the European colonization of the Americas, the Caribbean became the world's largest source of sugar. These islands could supply sugar-cane using slave-labor and produce sugar at prices vastly lower than those of cane-sugar imported from the East. Thus the economies of entire islands such as Guadaloupe and Barbados became based on sugar-production. By 1750 the French colony known as Saint-Domingue (subsequently the independent country of Haiti) became the largest sugar-producer in the world. Jamaica too became a major producer in the 18th century. Sugar-plantations fueled a demand for manpower; between 1701 and 1810 ships brought nearly one million slaves to work in Jamaica and in Barbados.
During the eighteenth century, sugar became enormously popular and the sugar-market went through a series of booms. The heightened demand and production of sugar came about to a large extent due to a great change in the eating habits of many Europeans. For example, they began consuming jams, candy, tea, coffee, cocoa, processed foods, and other sweet victuals in much greater numbers. Reacting to this increasing craze, the islands took advantage of the situation and began producing more sugar. In fact, they produced up to ninety percent of the sugar that the western Europeans consumed. Some islands proved more successful than others when it came to producing the product. And in Barbados and the British Leeward Islands sugar provided 93% and 97% respectively of exports.
Planters later began developing ways to boost production even more. For example, they began using more manure when growing their crops. They also developed more advanced mills and began using better types of sugar-cane. Despite these and other improvements, the price of sugar reached soaring heights, especially during events such as the revolt against the Dutch and the Napoleonic Wars. Sugar remained in high demand, and the islands' planters knew exactly how to take advantage of the situation.
As Europeans established sugar-plantations on the larger Caribbean islands, prices fell, especially in Britain. By the eighteenth century all levels of society had become common consumers of the former luxury product. At first most sugar in Britain went into tea, but later confectionery and chocolates became extremely popular. Many Britons (especially children) also ate jams. Suppliers commonly sold sugar in solid cones and consumers required a sugar nip, a pliers-like tool, to break off pieces.
Sugar-cane quickly exhausts the soil in which it grows, and planters pressed larger islands with fresher soil into production in the nineteenth century. In this century, for example, Cuba rose to become the richest land in the Caribbean (with sugar as its dominant crop) because it formed the only major island land-mass free of mountainous terrain. Instead, nearly three-quarters of its land formed a rolling plain — ideal for planting crops. Cuba also prospered above other islands because Cubans used better methods when harvesting the sugar crops: they adopted modern milling-methods such as water-mills, enclosed furnaces, steam-engines, and vacuum-pans. All these technologies increased productivity.
After the Haïtian Revolution established the independent state of Haiti, sugar production in that country declined and Cuba replaced Saint-Domingue as the world's largest producer.
Long established in Brazil, sugar-production spread to other parts of South America, as well as to newer European colonies in Africa and in the Pacific, where it became especially important in Fiji.
In Colombia, the planting of sugar started very early on, and entrepreneurs imported many African slaves to cultivate the fields. The industrialization of the Colombian industry started in 1901 with the establishment of the first steam-powered sugar mill by Santiago Eder.
## The rise of beet sugar
In 1747 the German chemist Andreas Marggraf identified sucrose in beet-root. This discovery remained a mere curiosity for some time, but eventually Marggraf's student Franz Achard built a sugarbeet-processing factory at Cunern in Silesia, under the patronage of King Frederick William III of Prussia (reigned 1797 - 1840). While never profitable, this plant operated from 1801 until it suffered destruction during the Napoleonic Wars (ca 1802 - 1815).
Napoleon, cut off from Caribbean imports by a British blockade and at any rate not wanting to fund British merchants, banned imports of sugar in 1813. The beet-sugar industry that emerged in consequence grew, and today sugar-beet provides approximately 30% of world sugar production.
While no longer grown by slaves, sugar from developing countries has an on-going association with workers earning minimal wages and living in extreme poverty.
In the developed countries, the sugar industry relies on machinery, with a low requirement for manpower. A large beet-refinery producing around 1,500 tonnes of sugar a day needs a permanent workforce of about 150 for 24-hour production.
## Mechanization
Beginning in the late 18th century, the production of sugar became increasingly mechanized. The steam engine first powered a sugar-mill in Jamaica in 1768, and soon after, steam replaced direct firing as the source of process heat.
In 1813 the British chemist Edward Charles Howard invented a method of refining sugar that involved boiling the cane juice not in an open kettle, but in a closed vessel heated by steam and held under partial vacuum. At reduced pressure, water boils at a lower temperature, and this development both saved fuel and reduced the amount of sugar lost through caramelization. Further gains in fuel-efficiency came from the multiple-effect evaporator, designed by the African-American engineer Norbert Rillieux (perhaps as early as the 1820s, although the first working model dates from 1845). This system consisted of a series of vacuum pans, each held at a lower pressure than the previous one. The vapors from each pan served to heat the next, with minimal heat wasted. Today, many industries use multiple-effect evaporators for evaporating water.
The process of separating sugar from molasses also received mechanical attention: David Weston first applied the centrifuge to this task in Hawaii in 1852.
# Etymology
The English word "sugar" originates from the Arabic and Persian word shakar.[1] It came to English by way of French, Spanish and/or Italian, which derived their word for sugar from the Arabic and Persian shakar (whence the Portuguese word açúcar, the Spanish word azúcar, the Italian word zucchero, the Old French word zuchre and the contemporary French word sucre). (Compare the OED.) The Greek word for "sugar" is zahari, which means "sugar" or "pebble". Note that the English word jaggery (meaning "coarse brown Indian sugar") has similar ultimate etymological origins (presumably in Sanskrit).
# Sugar as food
Originally a luxury, sugar eventually became sufficiently cheap and common to influence standard cuisine. Britain and the Caribbean islands have cuisines where the use of sugar become particularly prominent.
Sugar forms a major element in confectionery and in desserts. Cooks use it as a food preservative as well as for sweetening.
## Concerns of vegetarians and vegans
The sugar-refining industry often uses bone char (calcinated animal bones) for decolorizing. This concerns vegans and vegetarians; about a quarter of the sugar in the U.S. gets processed using bone char as a filter and the rest gets processed with activated carbon. As bone char does not get into the sugar, the relevant authorities consider sugar processed this way as parve/kosher.
Vegetarians and vegans may also object to the impact that the burning of the cane fields (a common part of the harvesting practice) has on insects, rats, snakes, and other life residing in the fields.[2]
The killing of such species parallels the killing of bees in the course of the production of honey, another sweetener that vegans usually avoid.
# Sugar and health
Whereas historically rotting teeth once seemed the most prominent health-hazard from the use of sugar, first the growth in the usage of rum (a sugar-cane derivative) and then concerns about type 2 diabetes and obesity have gradually come into prominence.
## Tooth-decay
Tooth-decay, arguably the most prominent health hazard associated with the use of sugar, can damage teeth in many ways. Bacteria in the mouth metabolize sugar into various acids. When the pH at the surface of the tooth drops below 5.5 (known as the "critical pH"), the acids start dissolving tooth-enamel. This results in decay of the tooth.
## Diabetes
Diabetes, a disease that causes the body to metabolize sugar poorly, occurs when either:
- the body's cells ignore insulin, a chemical that allows the metabolizing of sugar (Type 2 diabetes)
- the body attacks the cells producing the insulin (Type 1 diabetes)
When glucose builds up in the bloodstream, it can cause two problems:
- in the short term, cells become starved for energy because they do not have access to the glucose
- in the long term, frequent glucose build-up can damage many of the body's organs, including the eyes, kidneys, nerves and/or heart
However, while sugars may adversely affect those with diabetes, science has not proven that sugars cause diabetes.
## Obesity
In the United States of America, a scientific/health debate has startedover the causes of a steep rise in obesity in the general population — and one view posits increased consumption of carbohydrates in recent decades as a major factor.[3]
Obesity can result from a number of factors including:
- an increased intake of energy-dense foods — high in fat and sugars but low in vitamins, minerals and other micronutrients; and
- decreased physical activity.[4]
## United Nations nutritional advice
In 2003, four United Nations agencies, (including the World Health Organization (WHO) and the Food and Agriculture Organization (FAO)) commissioned a report compiled by a panel of 30 international experts. The panel stated that the total of free sugars (all monosaccharides and disaccharides added to foods by manufacturers, cooks or consumers, plus sugars naturally present in honey, syrups and fruit juices) should not account for more than 10% of the energy intake of a healthy diet, while carbohydrates in total should represent between 55% and 75% of the energy-intake (table 6, page 56 of the WHO Technical Report Series 916, Diet, Nutrition and the Prevention of Chronic Diseases: see http://www.fao.org/docrep/005/AC911E/ac911e07.htm#bm07.1.3 ).
## Sugar producers’ nutritional advice
In contradistinction to the United Nations report, the Sugar Association of the United States of America insists that other evidence indicates that a quarter of human food and drink intake can safely consist of sugar.
## Debate on extrinsic sugar
Argument continues as to the value of extrinsic sugar (sugar added to food) compared to that of intrinsic sugar (sugars - seldom sucrose - naturally present in food). Adding sugar to food particularly enhances taste, but has drawbacks of boosting calories, among other negative effects on health and physiology.
In the United States of America, sugar has become increasingly evident in food products, as more food-manufacturers add sugar or high-fructose corn-syrup to a wide variety of consumables. Candy-bars, soft drinks, chips, snacks, fruit-juice, peanut-butter, soups, ice-cream, jams, jellies, yogurt, and many breads have added sugars. Five Alive, for example, portrayed by its suppliers as "all natural" and featuring pictures of five different types of fruit on its label, comprises only 41% fruit juice, having high-fructose corn-syrup as its prime ingredient.
Many doctors argue that health authorities should classify sugar and high-fructose corn-syrup as food additives.[5]
Some go so far as to call refined sugar a poison.[6]
The anthropologist and dentist Weston A. Price, writing in 1939,[7]
correlated the use of refined sugar (and refined grains) with malnutrition in pregnant women, malformation of the palate and jaw in their children, followed by cramping of teeth in adolescence (leading to crooked teeth and the removal of wisdom teeth molars). Price correlated other ailments and the impaired function of the pituitary or master gland with consumption of refined sugar, as well as rates of infant mortality, subnormal intelligence, delinquency, and incarceration. He also correlated the underdevelopment of the pelvis, which in women would lead to complications (pain, death, etc.) in childbirth.
Virtually all of these symptoms became the norm in modern populations consuming typical amounts of refined sugar and other "modern foods of commerce". Besides the rotting of teeth, interruptible or resumable merely by removing or re-introducing white sugar into a diet, the correlations with consumption of refined sugar may relate less to the consumption of refined sugar itself than to the absence of the consumption of "nourishment", a category in which Price did not include refined sugar.
## Nutrition
Sugar-cane in its natural form provides a rich source of vitamins and minerals, but refined sugar lacks many nutrients.
## Sugar and hyperactivity
Sugar (not only sucrose, but also other varieties such as glucose) may cause some children to become hyperactive — giving rise to the terms "sugar high", "sugar rush" and "sugar buzz". Recent studies financed by the sugar-industry found that in a party situation all children became very active after only some had consumed sugar, thus demonstrating the lack of a direct link between individual consumption of sugar and individual levels of hyperactivity in that party context, even when the researchers focused on children with a presumed "sugar-sensitivity". If sugar-industry researchers believe sugar does not contribute to hyperactivity, or if parents and teachers believe in the possibility of a sugar-high, their respective biases may cause them to perceive children accordingly after consumption of sweets and sugary beverages through observer-bias. (Note that the experiments did not take place in the context of a control-group following a base diet-level matching the recommendation of the WHO/FAO (stated above) to avoid the impacts of added extrinsic sugars cited above, nor in a controlled setting — and so could not give credible results.)
Some commentators believe that children and adults show the hyperactive effects of sugar equally. On average, Americans eat or drink approximately five pounds of sugar a month.[8]
# Production
Table sugar (sucrose) comes from plant sources. Two important sugar crops predominate: sugarcane (Saccharum spp.) and sugar beets (Beta vulgaris), in which sugar can account for 12% to 20% of the plant's dry weight. Some minor commercial sugar crops include the date palm (Phoenix dactylifera), sorghum (Sorghum vulgare), and the sugar maple (Acer saccharum). In the financial year 2001/2002, worldwide production of sugar amounted to 134.1 million tonnes.
The first production of sugar from sugar-cane took place in India. Alexander the Great's companions reported seeing "honey produced without the intervention of bees" and it remained exotic in Europe until the Arabs started cultivating it in Sicily and Spain. Only after the Crusades did it begin to rival honey as a sweetener in Europe. The Spanish began cultivating sugar-cane in the West Indies in 1506 (and in Cuba in 1523). The Portuguese first cultivated sugar-cane in Brazil in 1532.
Most cane-sugar comes from countries with warm climates, such as Brazil, India, China, Thailand, Mexico and Australia, the five top sugar producing countries in the world.[9] Brazil overshadows most countries with roughly 30 million tonnes of cane sugar produced in 2006, while India produced 21 million, China 11 million, and Thailand and Mexico at roughly 5 million. Viewed by region, Asia is the world-leader in cane-sugar production with large contributions from China, India and Thailand and other countries combining to account for 40% of global production in 2006. South America comes in second place with 32% of global production, Africa and Central America both at 8% and Australia at 5%. The United States, the Caribbean and Europe make up the remainder with roughly 3% each.[10]
Beet-sugar comes from regions with cooler climates: northwest and eastern Europe, northern Japan, plus some areas in the United States (including California). In the northern hemisphere, the beet-growing season ends with the start of harvesting around September. Harvesting and processing continues until March in some cases. The availability of processing-plant capacity, and the weather both influence the duration of harvesting and processing - the industry can lay up harvested beet until processed, but frost-damaged beet becomes effectively unprocessable.
The European Union (EU) has become the world's second-largest sugar exporter. The Common Agricultural Policy of the EU sets maximum quotas for members' production to match supply and demand, and a price. Europe exports excess production quota (approximately 5 million tonnes in 2003). Part of this, "quota" sugar, gets subsidised from industry levies, the remainder (approximately half) sells as "C quota" sugar at market prices without subsidy. These subsidies and a high import tariff make it difficult for other countries to export to the EU states, or to compete with the Europeans on world markets.
The United States sets high sugar prices to support its producers, with the effect that many former consumers of sugar have switched to corn syrup (beverage-manufacturers) or moved out of the country (candy-makers).
The cheap prices of glucose syrups produced from wheat and corn (maize) threaten the traditional sugar market. In combination with artificial sweeteners, drink manufacturers can produce very low-cost products.
## Cane
Since the 6th century BC cane-sugar producers have crushed the harvested vegetable material from sugar-cane in order to collect and filter the juice. They then treat the liquid (often with lime (calcium oxide)) to remove impurities and then neutralize it. Boiling the juice then allows the sediment to settle to the bottom for dredging out, while the scum rises to the surface for skimming off. In cooling, the liquid crystallizes, usually in the process of stirring, to produce sugar crystals. Centrifuges usually remove the uncrystallized syrup. The producers can then either sell the resultant sugar, as is, for use; or process it further to produce lighter grades. This processing may take place in another factory in another country.
## Beet
Beet-sugar producers slice the washed beets, then extract the sugar with hot water in a "diffuser". An alkaline solution ("milk of lime" and carbon dioxide from the lime kiln) then serves to precipitate impurities (see carbonatation). After filtration, evaporation concentrates the juice to a content of about 70% solids, and controlled crystallisation extracts the sugar. A centrifuge removes the sugar crystals from the liquid, which gets recycled in the crystalliser stages. When economic constraints prevent the removal of more sugar, the manufacturer discards the remaining liquid, now known as molasses.
Sieving the resultant white sugar produces different grades for selling.
## Cane versus beet
Little perceptible difference exists between sugar produced from beet and that from cane. Tests can distinguish the two, and some tests aim to detect fraudulent abuse of EU subsidies or to aid in the detection of adulterated fruit-juice.
The production of sugar results in residues which differ substantially depending on the raw materials used and on the place of production. While cooks often use cane molasses in food, humans find molasses from sugar beet unpalatable, and it therefore ends up mostly as industrial fermentation feedstock, or as animal-feed. Once dried, either type of molasses can serve as fuel for burning.
## Culinary sugars
So-called raw sugars comprise yellow to brown sugars made by clarifying the source syrup by boiling and drying with heat, until it becomes a crystalline solid, with minimal chemical processing. Raw beet sugars result from the processing of sugar-beet juice, but only as intermediates en route to white sugar. Types of raw sugar include demerara, muscovado, and turbinado. Mauritius and Malawi export significant quantities of such specialty sugars. Manufacturers sometimes prepare raw sugar as loaves rather than as a crystalline powder, by pouring sugar and molasses together into molds and allowing the mixture to dry. This results in sugar-cakes or loaves, called jaggery or gur in India, pingbian tang in China, and panela, panocha, pile, piloncillo and pão-de-açúcar in various parts of Latin America. In South America, truly raw sugar, unheated and made from sugar-cane grown on farms, does not have a large market-share.
Mill white sugar, also called plantation white, crystal sugar, or superior sugar, consists of raw sugar where the production process does not remove colored impurities, but rather bleaches them white by exposure to sulfur dioxide. Though the most common form of sugar in sugarcane-growing areas, this product does not store or ship well; after a few weeks, its impurities tend to promote discoloration and clumping.
Blanco directo, a white sugar common in India and other south Asian countries, comes from precipitating many impurities out of the cane juice by using phosphatation — a treatment with phosphoric acid and calcium hydroxide similar to the carbonatation technique used in beet-sugar refining. In terms of sucrose purity, blanco directo is more pure than mill white, but less pure than white refined sugar.
White refined sugar has become the most common form of sugar in North America as well as in Europe. Refined sugar can be made by dissolving raw sugar and purifying it with a phosphoric acid method similar to that used for blanco directo, a carbonatation process involving calcium hydroxide and carbon dioxide, or by various filtration strategies. It is then further purified by filtration through a bed of activated carbon or bone char depending on where the processing takes place. Beet sugar refineries produce refined white sugar directly without an intermediate raw stage. White refined sugar is typically sold as granulated sugar, which has been dried to prevent clumping.
Granulated sugar comes in various crystal sizes — for home and industrial use — depending on the application:
- Coarse-grained sugars, such as sanding sugar (nibbed sugar or sugar nibs) find favor for decorating cookies/biscuits and other desserts.
- Normal granulated sugars for table use: typically they have a grain size about 0.5 mm across
- Finer grades result from selectively sieving the granulated sugar
caster (or castor[11]) (0.35 mm), commonly used in baking
superfine sugar, also called baker's sugar, berry sugar, or bar sugar — favored for sweetening drinks or for preparing meringue
- caster (or castor[11]) (0.35 mm), commonly used in baking
- superfine sugar, also called baker's sugar, berry sugar, or bar sugar — favored for sweetening drinks or for preparing meringue
- Finest grades
Powdered sugar, 10X sugar, confectioner's sugar (0.060 mm), or icing sugar (0.024 mm), produced by grinding sugar to a fine powder. The manufacturer may add a small amount of anti-caking agent to prevent clumping — either cornstarch (1% to 3%) or tri-calcium phosphate. File:Sugarcubes.jpgSugar-cubes close-up.
- Powdered sugar, 10X sugar, confectioner's sugar (0.060 mm), or icing sugar (0.024 mm), produced by grinding sugar to a fine powder. The manufacturer may add a small amount of anti-caking agent to prevent clumping — either cornstarch (1% to 3%) or tri-calcium phosphate. File:Sugarcubes.jpgSugar-cubes close-up.
Retailers also sell sugar cubes or lumps for convenient consumption of a standardised amount. Suppliers of sugar-cubes make them by mixing sugar crystals with sugar syrup. Jakub Kryštof Rad invented sugar-cubes in 1841.
Brown sugars come from the late stages of sugar refining, when sugar forms fine crystals with significant molasses-content, or from coating white refined sugar with a cane molasses syrup. Their color and taste become stronger with increasing molasses-content, as do their moisture-retaining properties. Brown sugars also tend to harden if exposed to the atmosphere, although proper handling can reverse this.
The World Health Organisation and the Food and Agriculture Organization of the United Nations expert report (WHO Technical Report Series 916 Diet, Nutrition and the Prevention of Chronic Diseases) defines free sugars as all monosaccharides and disaccharides added to foods by the manufacturer, cook or consumer, plus sugars naturally present in honey, syrups and fruit-juices. This includes all the sugars referred to above. The term distinguishes these forms from all other culinary sugars added in their natural form with no refining at all.
Natural sugars comprise all completely unrefined sugars: effectively all sugars not defined as free sugars. The WHO Technical Report Series 916 Diet, Nutrition and the Prevention of Chronic Diseases approves only natural sugars as carbohydrates for unrestricted consumption. Natural sugars come in fruit, grains and vegetables in their natural or cooked form.
# Chemistry
Biochemists regard sugars as relatively simple carbohydrates. Sugars include monosaccharides, disaccharides, trisaccharides and the oligosaccharides - containing 1, 2, 3, and 4 or more monosaccharide units respectively. Sugars contain either aldehyde groups (-CHO) or ketone groups (C=O), where there are carbon-oxygen double bonds, making the sugars reactive. Most simple sugars (monosaccharides) conform to (CH2O)n where n is between 3 and 7. A notable exception, deoxyribose, as its name suggests, has a "missing" oxygen atom. All saccharides with more than one ring in their structure result from two or more monosaccharides joined by glycosidic bonds with the resultant loss of a molecule of water (H2O) per bond.
As well as using classifications based on their reactive group, chemists may also subdivide sugars according to the number of carbons they contain. Derivatives of trioses (C3H6O3) are intermediates in glycolysis. Pentoses (5-carbon sugars) include ribose and deoxyribose, which form part of nucleic acids. Ribose also forms a component of several chemicals that have importance in the metabolic process, including NADH and ATP. Hexoses (6-carbon sugars) include glucose, a universal substrate for the production of energy in the form of ATP. Through photosynthesis plants produce glucose, which has the formula C6H12O6, and then convert it for storage as an energy-reserve in the form of other carbohydrates such as starch, or (as in cane and beet) as sucrose (table sugar). The chemical formula for sucrose is C12H22O11.
Many pentoses and hexoses can form ring structures. In these closed-chain forms, the aldehyde or ketone group remains unfree, so many of the reactions typical of these groups cannot occur. Glucose in solution exists mostly in the ring form at equilibrium, with less than 0.1% of the molecules in the open-chain form.
Monosaccharides in a closed-chain form can form glycosidic bonds with other monosaccharides, creating disaccharides (such as sucrose) and polysaccharides (such as starch). Enzymes must hydrolyse or otherwise break these glycosidic bonds before such compounds will be metabolised. After digestion and absorption. the principal monosaccharides present in the blood and internal tissues include glucose, fructose, and galactose.
The prefix "glyco-" indicates the presence of a sugar in an otherwise non-carbohydrate substance. Note for example glycoproteins, proteins which are connected to one or more sugars.
Monosaccharides include fructose, glucose, galactose and mannose. Disaccharides occur most commonly as sucrose (cane or beet sugar - made from one glucose and one fructose), lactose (milk sugar - made from one glucose and one galactose) and maltose (made of two glucoses). These disaccharides have the formula C12H22O11.
Hydrolysis can convert sucrose into a syrup of fructose and glucose, producing invert sugar. This resulting syrup, sweeter than the original sucrose, has uses in making confections because it does not crystallize as easily and thus produces a smoother finished product.
# Measuring sugar
See also International Commission for Uniform Methods of Sugar Analysis
## Dissolved sugar content
Scientists use degrees Brix (symbol °Bx), introduced by Antoine Brix, as units of measurement of the mass ratio of dissolved substance to water in a liquid. A 25 °Bx sucrose solution has 25 grams of sucrose per 100 grams of liquid; or, to put it another way, 25 grams of sucrose sugar and 75 grams of water exist in the 100 grams of solution.
An infrared Brix sensor measures the vibrational frequency of the sugar molecules, giving a Brix degrees measurement. This does not equate to Brix degrees from a density or refractive index measurement because it will specifically measure dissolved sugar concentration instead of all dissolved solids. When using a refractometer, one should report the result as "refractometric dried substance" (RDS). One might speak of a liquid as having 20 °Bx RDS. This refers to a measure of percent by weight of total dried solids and, although not technically the same as Brix degrees determined through an infrared method, renders an accurate measurement of sucrose content, since sucrose in fact forms the majority of dried solids. The advent of in-line infrared Brix measurement sensors has made measuring the amount of dissolved sugar in products economical using a direct measurement.
## Sugar purity
Technicians usually measure the purity of sugar, i.e. the sucrose content, by polarimetry — the measurement of the rotation of plane-polarized light by a solution of sugar.
# Sugar economics
Historically one of the most widely-traded commodities in the world, sugar accounts for around 2% of the global dry cargo market. International sugar prices show great volatility, ranging from around 3 to over 60 cents per pound in the past 50 years. Of the world's 180-odd countries, around 100 produce sugar from beet or cane, a few more refine raw sugar to produce white sugar, and all countries consume sugar. Consumption of sugar ranges from around 3 kilograms per person per annum in Ethiopia to around 40 kg/person/yr in Belgium. Consumption per capita rises with income per capita until it reaches a plateau of around 35kg per person per year in middle-income countries.
Many countries subsidize sugar-production heavily. The European Union, the United States, Japan and many developing countries subsidize domestic production and maintain high tariffs on imports. Sugar prices in these countries have often exceeded prices on the international market by up to three times; today, with world market sugar futures prices currently strong, such prices typically exceed world prices by two times.
Within international trade bodies, especially in the World Trade Organization, the "G20" countries led by Brazil have long argued that because these sugar markets essentially exclude cane-sugar imports, the G20 sugar-producers receive lower prices than they would under free trade. While both the European Union and United States maintain trade agreements whereby certain developing and less-developed countries (LDCs) can sell certain quantities of sugar into their markets, free of the usual import tariffs, countries outside these preferred trade régimes have complained that these arrangements violate the "most favoured nation" principle of international trade.
In 2004, the WTO sided with a group of cane-sugar exporting nations (led by Brazil and Australia) and ruled the EU sugar-régime and the accompanying ACP-EU Sugar Protocol (whereby a group of African, Caribbean, and Pacific countries receive preferential access to the European sugar market) illegal.[12] In response to this and to other rulings of the WTO, and owing to internal pressures on the EU sugar-régime, the European Commission proposed on 22 June 2005 a radical reform of the EU sugar-régime, cutting prices by 39% and eliminating all EU sugar exports.[13]
The African, Caribbean, Pacific and least developed country sugar-exporters reacted with dismay to the EU sugar proposals,[14]. On 25 November 2005 the Council of the EU agreed to cut EU sugar-prices by 36% as from 2009. It now seems[15] that the U.S. Sugar Program could become the next target for reform. However, some commentators expect heavy lobbying from the U.S. sugar-industry, which donated $2.7 million to House and Senate incumbents in the 2006 election, more than any other group of US food growers.[16] Especially prominent in this group are The Fanjul Brothers, sugar barons who are the single largest individual contributors of soft money to both the Democratic and Republican parties in the political system of the United States of America.[17][18]
Small quantities of sugar, especially specialty grades of sugar, reach the market as 'fair trade' commodities; the fair-trade system produces and sells these products with the understanding that a larger-than-usual fraction of the revenue will support small farmers in the developing world. However, whilst the Fairtrade Foundation offers a premium of USD 60.00 per tonne to small farmers for sugar branded as "Fairtrade",[19]
government schemes such the U.S. Sugar Program and the ACP Sugar Protocol offer premiums of around USD 400.00 per tonne above world market prices. However, the EU announced on 14 September 2007 that it would denounce the ACP Sugar Protocol with effect from 1 October 2009.[20][21]
The Sugar Association has launched a campaign to promote sugar over artificial substitutes. The Association now aggressively challenges many common beliefs regarding negative side effects of sugar consumption. The campaign aired a high-profile television-commercial during the 2007 Prime Time Emmy Awards on FOX Television. The Sugar Association uses the trademark tagline "Sugar: sweet by nature."[22] | https://www.wikidoc.org/index.php/Sugar | |
6b10b52f89412b139e9db2ad3f866b6ad73fa7c8 | wikidoc | Susto | Susto
# Background
Susto is as a folk illness, specifically a "fright sickness" with strong psychological overtones. Susto comes from the Spanish word for "fright" (i.e. Sudden intense fear, as of something immediately threatening). A more severe and potentially fatal form of susto is called espanto (also from Spanish, meaning terror or intense fright). People believe that if a person is suffering from susto, his or her soul is separated from the body.
Those most likely to suffer from susto are culturally stressed adults (women more often than men). Occasionally children can suffer susto as well. Etiology generally includes a sudden frightening experience such as an accident, a fall, witnessing a relative's sudden death, or any other potentially dangerous event. Researches show that knowledge of the existence of susto is a major contributing factor in improving the condition.
Symptoms of susto are thought to include nervousness, anorexia, insomnia, listlessness, despondency, involuntary muscle tics, and diarrhea. Treatments include the consumption of orange blossom, brazil wood or marijuana teas. An oral solution of figs boiled in vinegar is also imagined to be somewhat therapeutic.
The cure that is the most effective is a ceremony known as limpieza (Spanish for "cleansing" (noun)) or barrida (Spanish for "sweeping" (noun)), which may not be entirely successful the first few times it is attempted. The limpia or barrida is considered to be best administered immediately after the traumatic event occurs, and is ideally conducted by a curandero (healer). During the limpia/barrida, the patient recounts the details of the frightening event, then lies down on the floor on the axis of a crucifix. The curandero may have the crucifix outlined with aluminum foil or other shiny material. The victim's body is then brushed with a bouquet of fresh herbs such as basil, purple sage, rosemary or rue, while the curandero and other participants recite prayers. Depending on local custom, the curandero may also jump over the victims's body. This is thought by some to exhort the frightened soul back into the body.
Given the fact that there is not a complete universal understanding of this illness and that the symptoms vary from culture to culture is in part what classifies susto as a folk illness. Some treatment is as simple as drinking tea made from lemon or vinegar but for more severe cases a healer or curandera is brought in to perform specific ceremonies.
Traditional Western medicine has not yet recognized susto but there are some similarities between susto and some stress disorders. Many anthropologists feel that susto is the Latin American version of schizophrenia. “Post-traumatic Stress Disorder” and “Acute Stress Disorder” in particular share some similarities to the condition known as susto. According to the Diagnostic and Statistical Manual of Mental Disorders IV TR(DSM-IV-TR) fourth edition Post-traumatic Stress Disorder is associated with increased rates of "Major Depressive Disorder", "Generalized Anxiety Disorder", and "Social Phobia". The DSM-IV-TR also states that certain forms of Post-traumatic Stress Disorder can have characteristic symptoms which include diminished participation in significant activities, feeling of detachment from others, and difficulty falling or staying asleep. | Susto
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Susto is as a folk illness, specifically a "fright sickness" with strong psychological overtones. Susto comes from the Spanish word for "fright" (i.e. Sudden intense fear, as of something immediately threatening). A more severe and potentially fatal form of susto is called espanto (also from Spanish, meaning terror or intense fright). People believe that if a person is suffering from susto, his or her soul is separated from the body[citation needed].
Those most likely to suffer from susto are culturally stressed adults (women more often than men). Occasionally children can suffer susto as well. Etiology generally includes a sudden frightening experience such as an accident, a fall, witnessing a relative's sudden death, or any other potentially dangerous event. Researches show that knowledge of the existence of susto is a major contributing factor in improving the condition.
Symptoms of susto are thought to include nervousness, anorexia, insomnia, listlessness, despondency, involuntary muscle tics, and diarrhea. Treatments include the consumption of orange blossom, brazil wood or marijuana teas. An oral solution of figs boiled in vinegar is also imagined to be somewhat therapeutic.
The cure that is the most effective is a ceremony known as limpieza (Spanish for "cleansing" (noun)) or barrida (Spanish for "sweeping" (noun)), which may not be entirely successful the first few times it is attempted. The limpia or barrida is considered to be best administered immediately after the traumatic event occurs, and is ideally conducted by a curandero (healer). During the limpia/barrida, the patient recounts the details of the frightening event, then lies down on the floor on the axis of a crucifix. The curandero may have the crucifix outlined with aluminum foil or other shiny material. The victim's body is then brushed with a bouquet of fresh herbs such as basil, purple sage, rosemary or rue, while the curandero and other participants recite prayers. Depending on local custom, the curandero may also jump over the victims's body. This is thought by some to exhort the frightened soul back into the body.
Given the fact that there is not a complete universal understanding of this illness and that the symptoms vary from culture to culture is in part what classifies susto as a folk illness. Some treatment is as simple as drinking tea made from lemon or vinegar but for more severe cases a healer or curandera is brought in to perform specific ceremonies.
Traditional Western medicine has not yet recognized susto but there are some similarities between susto and some stress disorders. Many anthropologists feel that susto is the Latin American version of schizophrenia. “Post-traumatic Stress Disorder” and “Acute Stress Disorder” in particular share some similarities to the condition known as susto. According to the Diagnostic and Statistical Manual of Mental Disorders IV TR(DSM-IV-TR) fourth edition Post-traumatic Stress Disorder is associated with increased rates of "Major Depressive Disorder", "Generalized Anxiety Disorder", and "Social Phobia". The DSM-IV-TR also states that certain forms of Post-traumatic Stress Disorder can have characteristic symptoms which include diminished participation in significant activities, feeling of detachment from others, and difficulty falling or staying asleep. | https://www.wikidoc.org/index.php/Susto | |
b5651250ce77d5118fc75cca8f1992b51fc17357 | wikidoc | Syrup | Syrup
In cooking, a syrup (from Arabic شراب sharab, beverage, via Latin siropus) is a thick, viscous liquid, containing a large amount of dissolved sugars, but showing little tendency to deposit crystals. The viscosity arises from the multiple hydrogen bonds between the dissolved sugar, which has many hydroxyl (OH) groups, and the water. Technically and scientifically, the term syrup is also employed to denote viscous, generally residual, liquids, containing substances other than sugars in solution. Artificial maple syrup is made with water and an extremely large amount of dissolved sugar. The solution is heated so more sugar can be put in than normally possible. The solution becomes super-saturated.
# Pharmaceutical syrup
The syrup employed as a base for medicinal purposes consists of a concentrated or saturated solution of refined sugar in distilled water. The "simple syrup" of the British Pharmacopoeia is prepared by adding 1 kg of refined sugar to 500 mL of boiling distilled water, heating until it is dissolved and subsequently adding boiling distilled water until the weight of the whole is 1.5 kg. The specific gravity of the syrup should be 1.33. This is a 66° Brix solution.
Flavoured syrups are made by adding flavouring matter to a simple syrup. For instance, syrupus aromaticus is prepared by adding certain quantities of orange flavouring and cinnamon water to simple syrup. Similarly, medicated syrups are prepared by adding medicaments to, or dissolving them in, the simple syrup.
# Culinary syrup
Golden syrup is a by-product of the process of obtaining refined crystallized sugar. Molasses is a syrup obtained at a different stage of refining.
Karo Syrup is a brand of thick corn syrup made from a concentrated solution of dextrose and other sugars derived from corn starch with preservatives and flavourings. It is a staple of Southern United States cuisine, e.g., to make pecan pie, and is pronounced "kay-ro" in that region.
# Syrups for beverages
A variety of beverages call for sweetening to offset the tartness of some juices used in the drink recipes. Granulated sugar does not dissolve easily in cold drinks or ethyl alcohol. Since the following syrups are liquids, they are easily mixed with other liquids in mixed drinks, making them superior alternatives to granulated sugar.
## Simple syrup
Syrups used to make drinks at bars are referred to by several names. Sometimes they are called simple syrups. Other times they are called sugar syrups. Often these two names are combined to form the name simple sugar syrup. Because the syrup is often used to make alcoholic drinks, it is commonly referred to as bar syrup.
To make this bar syrup, gradually stir granulated sugar into hot water in a sauce pan until the sugar is dissolved, then remove from heat to cool. Generally, a ratio of two parts sugar to one part water is used.
This type of syrup is also common at coffee shops, especially in the United States where iced coffee is popular.
## Gomme syrup
Gomme syrup is an ingredient commonly used in mixed drinks. Like bar syrups, it is a sugar and water mixture, but has an added ingredient of Gum arabic which acts as an emulsifier. Gomme syrup is made with the highest percentage of sugar to water possible, while the gum arabic prevents the sugar from crystallizing and adds a smooth texture.
To make gomme syrup, bring sugar and water to a boil, then add gum powder dissolved in water. Drain for use. | Syrup
In cooking, a syrup (from Arabic شراب sharab, beverage, via Latin siropus) is a thick, viscous liquid, containing a large amount of dissolved sugars, but showing little tendency to deposit crystals. The viscosity arises from the multiple hydrogen bonds between the dissolved sugar, which has many hydroxyl (OH) groups, and the water. Technically and scientifically, the term syrup is also employed to denote viscous, generally residual, liquids, containing substances other than sugars in solution. Artificial maple syrup is made with water and an extremely large amount of dissolved sugar. The solution is heated so more sugar can be put in than normally possible. The solution becomes super-saturated.
# Pharmaceutical syrup
The syrup employed as a base for medicinal purposes consists of a concentrated or saturated solution of refined sugar in distilled water. The "simple syrup" of the British Pharmacopoeia is prepared by adding 1 kg of refined sugar to 500 mL of boiling distilled water, heating until it is dissolved and subsequently adding boiling distilled water until the weight of the whole is 1.5 kg. The specific gravity of the syrup should be 1.33. This is a 66° Brix solution.
Flavoured syrups are made by adding flavouring matter to a simple syrup. For instance, syrupus aromaticus is prepared by adding certain quantities of orange flavouring and cinnamon water to simple syrup. Similarly, medicated syrups are prepared by adding medicaments to, or dissolving them in, the simple syrup.
# Culinary syrup
Golden syrup is a by-product of the process of obtaining refined crystallized sugar. Molasses is a syrup obtained at a different stage of refining.
Karo Syrup is a brand of thick corn syrup made from a concentrated solution of dextrose and other sugars derived from corn starch with preservatives and flavourings. It is a staple of Southern United States cuisine, e.g., to make pecan pie, and is pronounced "kay-ro" in that region.
# Syrups for beverages
A variety of beverages call for sweetening to offset the tartness of some juices used in the drink recipes. Granulated sugar does not dissolve easily in cold drinks or ethyl alcohol. Since the following syrups are liquids, they are easily mixed with other liquids in mixed drinks, making them superior alternatives to granulated sugar.
## Simple syrup
Syrups used to make drinks at bars are referred to by several names. Sometimes they are called simple syrups. Other times they are called sugar syrups. Often these two names are combined to form the name simple sugar syrup. Because the syrup is often used to make alcoholic drinks, it is commonly referred to as bar syrup.
To make this bar syrup, gradually stir granulated sugar into hot water in a sauce pan until the sugar is dissolved, then remove from heat to cool. Generally, a ratio of two parts sugar to one part water is used.
This type of syrup is also common at coffee shops, especially in the United States where iced coffee is popular.
## Gomme syrup
Gomme syrup is an ingredient commonly used in mixed drinks. Like bar syrups, it is a sugar and water mixture, but has an added ingredient of Gum arabic which acts as an emulsifier. Gomme syrup is made with the highest percentage of sugar to water possible, while the gum arabic prevents the sugar from crystallizing and adds a smooth texture.
To make gomme syrup, bring sugar and water to a boil, then add gum powder dissolved in water. Drain for use.[1] | https://www.wikidoc.org/index.php/Syrup | |
a809df20ad1be45a75566ad5b3a2e9d8d7015aab | wikidoc | TAAR1 | TAAR1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.
TAAR1 is a high-affinity receptor for amphetamine, methamphetamine, dopamine, and trace amines which mediates some of their cellular effects in monoamine neurons within the central nervous system.
The primary endogenous ligands of the human TAAR1 (hTAAR1) receptor, by rank order of potency, are:tyramine > β-phenethylamine > dopamine = octopamine.
# Discovery
TAAR1 was discovered independently by Borowski et al. and Bunzow et al. in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.
# Structure
TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily. It has 7 transmembrane domains with short N and C terminal extensions. TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving. TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXXXXXXWF. TAAR1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction.
# Gene
All human TAAR genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons. The human TAAR1 gene is thought to be an intronless gene.
# Tissue distribution
To date, TAAR1 has been identified and cloned in five different mammal genomes: human, mouse, rat, monkey, and chimpanzee. In rats, mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the stomach, kidney, and lungs, and at low levels in the brain. Rhesus monkey Taar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of both species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus. hTAAR1 has also been identified in human astrocytes.
Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in the stomach, intestines, duodenum, pancreatic β-cells, and white blood cells. In the duodenum, TAAR1 activation increases glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) release; in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth hormone-inhibiting hormone) secretion from delta cells.
hTAAR1 is the only human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium.
## Location within neurons
TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals. In model cell systems, hTAAR1 has extremely poor membrane expression. A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.
Because TAAR1 is an intracellular receptor in monoamine neurons, exogenous TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux. Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron. The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons. E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal – markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.
## Receptor oligomers
TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo. These and other reported TAAR1 hetero-oligomers include:
- TAAR1–D2sh
- TAAR1–α2A
- TAAR1–TAAR2
# Ligands
## Agonists
### Trace amines
Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10 nM in the brain, constituting less than 1% of total biogenic amines in the mammalian nervous system. Some of the human trace amines include tryptamine, phenethylamine (PEA), N-methylphenethylamine, p-tyramine, m-tyramine, N-methyltyramine, p-octopamine, m-octopamine, and synephrine. These share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increased cyclic AMP (cAMP) concentration after the binding event.
The rank order of potency for the primary endogenous ligands at hTAAR1 is:tyramine > β-phenethylamine > dopamine = octopamine.
### Thyronamines
Thyronamines are molecular derivatives of the thyroid hormone and are very important for endocrine system function. 3-Iodothyronamine (T1AM) is the most potent TAAR1 agonist yet discovered, although it lacks monoamine transporter affinity and therefore has little effect in monoamine neurons of the central nervous system. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output.
### Synthetic
- Amphetamine and its substituted derivatives methamphetamine and MDMA are all potent hTAAR1 agonists. Upon association with TAAR1, they elicit increases in cAMP production similar to those of PEA and p-tyramine. These compounds are structurally similar to PEA and p-tyramine.
- Benzofurans: 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB, and 5-MAPDB, as well as the benzodifuran 2C-B-FLY, are hTAAR1 agonists that have an MDMA-like pharmacodynamic profile.
- The methylphenethylamines are agonists of hTAAR1; these include α-methylphenethylamine (amphetamine), β-methylphenethylamine, N-methylphenethylamine (a trace amine), 2-methylphenethylamine, 3-methylphenethylamine, and 4-methylphenethylamine.
- In rats, lysergic acid diethylamide (LSD) is an agonist of rTAAR1, but in humans it lacks any affinity for hTAAR1.
- Certain 2-aminooxazoline compounds (RO5166017, RO5256390, RO5203648, and RO5263397) are orally bioavailable, highly potent, and selective agonists of TAAR1 in laboratory animals.
RO5166017 or (S)-4--4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.
RO5203648 and RO5263397 are highly selective TAAR1 partial agonists. RO5203648 demonstrated clear antidepressant and anti-psychotic activity, additionally it attenuated drug self-administration and exhibited wakefulness promoting and cognition enhancing properties in murine and simian models.
- RO5166017 or (S)-4--4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.
- RO5203648 and RO5263397 are highly selective TAAR1 partial agonists. RO5203648 demonstrated clear antidepressant and anti-psychotic activity, additionally it attenuated drug self-administration and exhibited wakefulness promoting and cognition enhancing properties in murine and simian models.
## Inverse agonists
- EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective hTAAR1 inverse agonist.
## Neutral antagonists
As of early 2018, no neutral antagonists for hTAAR1 have been characterized.
# Function
## Monoaminergic systems
Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites. Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.
One of the downstream effects of active TAAR1 is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase. This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cell cytoplasm. These amines would then activate intracellular TAAR1. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons. As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.
In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby increasing post-synaptic receptor binding. Through direct activation of G protein-coupled inwardly-rectifying potassium channels (GIRKs), TAAR1 can reduce the firing rate of dopamine neurons, in turn preventing a hyper-dopaminergic state. Amphetamine and trace amines can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, these compounds activate TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).
## Immune system
Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics. In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades. In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system. A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.
Phytohaemagglutinin upregulates hTAAR1 mRNA in circulating leukocytes; in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists. TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells.
Astrocyte-localized TAAR1 regulates EAAT2 levels and function in these cells; this has been implicated in methamphetamine-induced pathologies of the neuroimmune system.
# Clinical significance
Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, and high concentrations are associated with schizophrenia. Low PEA levels and under-activation of TAAR1 also appears to be associated with ADHD. It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression. Some antidepressants function by inhibiting monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells. Decreased PEA metabolism has been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function. Mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.
Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.).
## Research
A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this possibly presents a target for therapeutic intervention.
In preclinical research on rats, TAAR1 activation in pancreatic cells promotes insulin, peptide YY, and GLP-1 secretion; therefore, TAAR1 is potentially a biological target for the treatment of obesity and diabetes.
# Notes
- ↑ In dopamine, norepinephrine, and serotonin neurons, the primary membrane transporters are DAT, NET, and SERT respectively.
- ↑ TAAR1–D2sh is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway. | TAAR1
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene.[1] TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (CNS).[2][3][4][5] TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al.[6][7] TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations.[8][9] TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS;[3][8] it also affects immune system and neuroimmune system function through different mechanisms.[10][11][12][13]
TAAR1 is a high-affinity receptor for amphetamine, methamphetamine, dopamine, and trace amines which mediates some of their cellular effects in monoamine neurons within the central nervous system.[3][8]
The primary endogenous ligands of the human TAAR1 (hTAAR1) receptor, by rank order of potency, are:tyramine > β-phenethylamine > dopamine = octopamine.[2]
# Discovery
TAAR1 was discovered independently by Borowski et al. and Bunzow et al. in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.[6][7]
# Structure
TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily.[7] It has 7 transmembrane domains with short N and C terminal extensions.[14] TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving.[6] TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction.[9]
# Gene
All human TAAR genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons.[9] The human TAAR1 gene is thought to be an intronless gene.[15]
# Tissue distribution
To date, TAAR1 has been identified and cloned in five different mammal genomes: human, mouse, rat, monkey, and chimpanzee. In rats, mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the stomach, kidney, and lungs, and at low levels in the brain.[6] Rhesus monkey Taar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of both species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus.[2][16] hTAAR1 has also been identified in human astrocytes.[2][10]
Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in the stomach, intestines, duodenum, pancreatic β-cells, and white blood cells.[5] In the duodenum, TAAR1 activation increases glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) release;[5] in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth hormone-inhibiting hormone) secretion from delta cells.[5]
hTAAR1 is the only human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium.[17]
## Location within neurons
TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals.[3][8][18] In model cell systems, hTAAR1 has extremely poor membrane expression.[18] A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.[18]
Because TAAR1 is an intracellular receptor in monoamine neurons, exogenous TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein[note 1] or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux.[8] Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron.[8] The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons.[8] E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal – markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.
## Receptor oligomers
TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo.[19][20] These and other reported TAAR1 hetero-oligomers include:
- TAAR1–D2sh[note 2][19]
- TAAR1–α2A[20]
- TAAR1–TAAR2[5]
# Ligands
## Agonists
### Trace amines
Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10 nM in the brain, constituting less than 1% of total biogenic amines in the mammalian nervous system.[22] Some of the human trace amines include tryptamine, phenethylamine (PEA), N-methylphenethylamine, p-tyramine, m-tyramine, N-methyltyramine, p-octopamine, m-octopamine, and synephrine. These share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increased cyclic AMP (cAMP) concentration after the binding event.
The rank order of potency for the primary endogenous ligands at hTAAR1 is:tyramine > β-phenethylamine > dopamine = octopamine.[2]
### Thyronamines
Thyronamines are molecular derivatives of the thyroid hormone and are very important for endocrine system function. 3-Iodothyronamine (T1AM) is the most potent TAAR1 agonist yet discovered, although it lacks monoamine transporter affinity and therefore has little effect in monoamine neurons of the central nervous system. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output.
### Synthetic
- Amphetamine and its substituted derivatives methamphetamine and MDMA are all potent hTAAR1 agonists.[3][5] Upon association with TAAR1, they elicit increases in cAMP production similar to those of PEA and p-tyramine.[5] These compounds are structurally similar to PEA and p-tyramine.[7][23]
- Benzofurans: 5-APB, 5-APDB, 6-APB, 6-APDB, 4-APB, 7-APB, 5-EAPB, and 5-MAPDB, as well as the benzodifuran 2C-B-FLY, are hTAAR1 agonists that have an MDMA-like pharmacodynamic profile.[24]
- The methylphenethylamines are agonists of hTAAR1; these include α-methylphenethylamine (amphetamine), β-methylphenethylamine, N-methylphenethylamine (a trace amine), 2-methylphenethylamine, 3-methylphenethylamine, and 4-methylphenethylamine.[25]
- In rats, lysergic acid diethylamide (LSD) is an agonist of rTAAR1,[7] but in humans it lacks any affinity for hTAAR1.[25]
- Certain 2-aminooxazoline compounds (RO5166017, RO5256390, RO5203648, and RO5263397) are orally bioavailable, highly potent, and selective agonists of TAAR1 in laboratory animals.[26]
RO5166017 or (S)-4-[(ethylphenylamino)methyl]-4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.[27]
RO5203648 and RO5263397 are highly selective TAAR1 partial agonists.[19] RO5203648 demonstrated clear antidepressant and anti-psychotic activity, additionally it attenuated drug self-administration and exhibited wakefulness promoting and cognition enhancing properties in murine and simian models.[28]
- RO5166017 or (S)-4-[(ethylphenylamino)methyl]-4,5-dihydrooxazol-2-ylamine is a selective TAAR1 agonist without significant activity at other targets.[27]
- RO5203648 and RO5263397 are highly selective TAAR1 partial agonists.[19] RO5203648 demonstrated clear antidepressant and anti-psychotic activity, additionally it attenuated drug self-administration and exhibited wakefulness promoting and cognition enhancing properties in murine and simian models.[28]
## Inverse agonists
- EPPTB or N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-trifluoromethylbenzamide is a selective hTAAR1 inverse agonist.[2][29]
## Neutral antagonists
As of early 2018,[update] no neutral antagonists for hTAAR1 have been characterized.[2]
# Function
## Monoaminergic systems
Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites.[22] Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.
One of the downstream effects of active TAAR1 is to increase cAMP in the presynaptic cell via Gαs G-protein activation of adenylyl cyclase.[6][7][9] This alone can have a multitude of cellular consequences. A main function of the cAMP may be to up-regulate the expression of trace amines in the cell cytoplasm.[23] These amines would then activate intracellular TAAR1. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[8] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[8][3] The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[8] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons.[8] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[8]
In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the synaptic cleft, thereby increasing post-synaptic receptor binding.[8] Through direct activation of G protein-coupled inwardly-rectifying potassium channels (GIRKs), TAAR1 can reduce the firing rate of dopamine neurons, in turn preventing a hyper-dopaminergic state.[27][32][33] Amphetamine and trace amines can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[8] As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[8] Upon entering the presynaptic neuron, these compounds activate TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[8][36]
## Immune system
Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics.[12] In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades.[12] In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system.[12] A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.[13]
Phytohaemagglutinin upregulates hTAAR1 mRNA in circulating leukocytes;[2] in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists.[2] TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells.[2]
Astrocyte-localized TAAR1 regulates EAAT2 levels and function in these cells;[10] this has been implicated in methamphetamine-induced pathologies of the neuroimmune system.[10]
# Clinical significance
Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder,[6][22][37] and high concentrations are associated with schizophrenia.[37][38] Low PEA levels and under-activation of TAAR1 also appears to be associated with ADHD.[37][38][39] It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression.[6][22] Some antidepressants function by inhibiting monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells.[6][9] Decreased PEA metabolism has been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function. Mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[9]
Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.).[3][4]
## Research
A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this possibly presents a target for therapeutic intervention.[40]
In preclinical research on rats, TAAR1 activation in pancreatic cells promotes insulin, peptide YY, and GLP-1 secretion;[41][non-primary source needed] therefore, TAAR1 is potentially a biological target for the treatment of obesity and diabetes.[41][non-primary source needed]
# Notes
- ↑ In dopamine, norepinephrine, and serotonin neurons, the primary membrane transporters are DAT, NET, and SERT respectively.[8]
- ↑ TAAR1–D2sh is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.[3][21] | https://www.wikidoc.org/index.php/TAAR1 | |
925b56f308e3a4b118e79ad73008ecd448cb0a71 | wikidoc | TAAR2 | TAAR2
Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene. TAAR2 is coexpressed with Gα proteins; however, as of February 2017, its signal transduction mechanisms have not been determined.
Human TAAR2 (hTAAR2) is expressed in the cerebellum, olfactory sensory neurons in the olfactory epithelium, and leukocytes (i.e., white blood cells), among other tissues. hTAAR1 and hTAAR2 are both required for white blood cell activation by trace amines in granulocytes.
A single nucleotide polymorphism nonsense mutation of the TAAR2 gene is associated with schizophrenia. TAAR2 is a probable pseudogene in 10–15% of Asians as a result of a polymorphism that produces a premature stop codon at amino acid 168. | TAAR2
Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene.[1][2][3][4] TAAR2 is coexpressed with Gα proteins;[4] however, as of February 2017,[update] its signal transduction mechanisms have not been determined.[4]
Human TAAR2 (hTAAR2) is expressed in the cerebellum, olfactory sensory neurons in the olfactory epithelium, and leukocytes (i.e., white blood cells), among other tissues.[5][6] hTAAR1 and hTAAR2 are both required for white blood cell activation by trace amines in granulocytes.[7]
A single nucleotide polymorphism nonsense mutation of the TAAR2 gene is associated with schizophrenia.[4][5] TAAR2 is a probable pseudogene in 10–15% of Asians as a result of a polymorphism that produces a premature stop codon at amino acid 168.[4] | https://www.wikidoc.org/index.php/TAAR2 | |
8cfd005f50f321d9ce0c25f53d126a141104c22d | wikidoc | TAF10 | TAF10
Transcription initiation factor TFIID subunit 10 is a protein that in humans is encoded by the TAF10 gene.
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the small subunits of TFIID that is associated with a subset of TFIID complexes. Studies with human and mammalian cells have shown that this subunit is required for transcriptional activation by the estrogen receptor, for progression through the cell cycle, and may also be required for certain cellular differentiation programs.
# Interactions
TAF10 has been shown to interact with TAF9, Transcription initiation protein SPT3 homolog, TAF13 and TATA binding protein. | TAF10
Transcription initiation factor TFIID subunit 10 is a protein that in humans is encoded by the TAF10 gene.[1][2]
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the small subunits of TFIID that is associated with a subset of TFIID complexes. Studies with human and mammalian cells have shown that this subunit is required for transcriptional activation by the estrogen receptor, for progression through the cell cycle, and may also be required for certain cellular differentiation programs.[2]
# Interactions
TAF10 has been shown to interact with TAF9,[3] Transcription initiation protein SPT3 homolog,[3][4] TAF13[5] and TATA binding protein.[6][7] | https://www.wikidoc.org/index.php/TAF10 | |
26e69082d0976b1e6ed75292b8c6791c812573e3 | wikidoc | TAF11 | TAF11
Transcription initiation factor TFIID subunit 11 also known as TAFII28, is a protein that in humans is encoded by the TAF11 gene.
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a small subunit of TFIID that is present in all TFIID complexes and interacts with TBP. This subunit also interacts with another small subunit, TAF13, to form a heterodimer with a structure similar to the histone core structure.
In molecular biology, TAFII28 refers to the TATA box binding protein associated factor. Together with the TATA-binding protein and other TAFs it forms the general transcription factor, TFIID. They together participate in the assembly of the transcription preinitiation complex. The conserved region is found at the C terminus of most member proteins.
# Structure
The crystal structure of hTAFII28 with hTAFII18 shows that this region is involved in the binding of these two subunits. The conserved region contains four alpha helices and three loops arranged as in histone H3.
# Interactions
TAF11 has been shown to interact with:
- GTF2F1,
- POLR2A and
- TAF13,
- TAF15,
- TATA binding protein, and
- Transcription Factor II B. | TAF11
Transcription initiation factor TFIID subunit 11 also known as TAFII28, is a protein that in humans is encoded by the TAF11 gene.[1][2][3]
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a small subunit of TFIID that is present in all TFIID complexes and interacts with TBP. This subunit also interacts with another small subunit, TAF13, to form a heterodimer with a structure similar to the histone core structure.[3]
In molecular biology, TAFII28 refers to the TATA box binding protein associated factor. Together with the TATA-binding protein and other TAFs it forms the general transcription factor, TFIID. They together participate in the assembly of the transcription preinitiation complex. The conserved region is found at the C terminus of most member proteins.
# Structure
The crystal structure of hTAFII28 with hTAFII18 shows that this region is involved in the binding of these two subunits. The conserved region contains four alpha helices and three loops arranged as in histone H3.[1][4]
# Interactions
TAF11 has been shown to interact with:
- GTF2F1,[5]
- POLR2A[5] and
- TAF13,[1][4]
- TAF15,[6]
- TATA binding protein,[1][7][8] and
- Transcription Factor II B.[5] | https://www.wikidoc.org/index.php/TAF11 | |
5759ed87b37d4be6ae2fcb0b01ee8f6ad20a8760 | wikidoc | TAF12 | TAF12
Transcription initiation factor TFIID subunit 12 is a protein that in humans is encoded by the TAF12 gene.
# Function
Control of transcription by RNA polymerase II involves the basal transcription machinery, which is a collection of proteins. These proteins with RNA polymerase II, assemble into complexes that are modulated by transactivator proteins that bind to cis-regulatory elements located adjacent to the transcription start site. Some modulators interact directly with the basal complex, whereas others may act as bridging proteins linking transactivators to the basal transcription factors. Some of these associated factors are weakly attached, whereas others are tightly associated with TBP in the TFIID complex. Among the latter are the TAF proteins. Different TAFs are predicted to mediate the function of distinct transcriptional activators for a variety of gene promoters and RNA polymerases. TAF12 interacts directly with TBP as well as with TAF2I.
# Interactions
TAF12 has been shown to interact with TAF9 and Transcription initiation protein SPT3 homolog. | TAF12
Transcription initiation factor TFIID subunit 12 is a protein that in humans is encoded by the TAF12 gene.[1][2]
# Function
Control of transcription by RNA polymerase II involves the basal transcription machinery, which is a collection of proteins. These proteins with RNA polymerase II, assemble into complexes that are modulated by transactivator proteins that bind to cis-regulatory elements located adjacent to the transcription start site. Some modulators interact directly with the basal complex, whereas others may act as bridging proteins linking transactivators to the basal transcription factors. Some of these associated factors are weakly attached, whereas others are tightly associated with TBP in the TFIID complex. Among the latter are the TAF proteins. Different TAFs are predicted to mediate the function of distinct transcriptional activators for a variety of gene promoters and RNA polymerases. TAF12 interacts directly with TBP as well as with TAF2I.[2]
# Interactions
TAF12 has been shown to interact with TAF9[3] and Transcription initiation protein SPT3 homolog.[3] | https://www.wikidoc.org/index.php/TAF12 | |
fc23251b792975924a9a616b81f32c52a613f7dd | wikidoc | TAF13 | TAF13
Transcription initiation factor TFIID subunit 13 is a protein that in humans is encoded by the TAF13 gene.
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a small subunit associated with a subset of TFIID complexes. This subunit interacts with TBP and with two other small subunits of TFIID, TAF10 and TAF11. There is a pseudogene located on chromosome 6.
# Interactions
TAF13 has been shown to interact with TAF15, TAF11, TAF10 and TATA binding protein. | TAF13
Transcription initiation factor TFIID subunit 13 is a protein that in humans is encoded by the TAF13 gene.[1][2]
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a small subunit associated with a subset of TFIID complexes. This subunit interacts with TBP and with two other small subunits of TFIID, TAF10 and TAF11. There is a pseudogene located on chromosome 6.[2]
# Interactions
TAF13 has been shown to interact with TAF15,[3] TAF11,[1][4] TAF10[1] and TATA binding protein.[1] | https://www.wikidoc.org/index.php/TAF13 | |
26de79db4ef4a3349bd381058026b5ca45361fe6 | wikidoc | TAF1A | TAF1A
TATA box-binding protein-associated factor RNA polymerase I subunit A is an enzyme that in humans is encoded by the TAF1A gene.
# Function
Initiation of transcription by RNA polymerase I requires the formation of a complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs) specific for RNA polymerase I. This complex, known as SL1, binds to the core promoter of ribosomal RNA genes to position the polymerase properly and acts as a channel for regulatory signals. This gene encodes the smallest SL1-specific TAF. Two transcripts encoding different isoforms have been identified.
# Interactions
TAF1A has been shown to interact with Acidic leucine-rich nuclear phosphoprotein 32 family member A and Protein SET. | TAF1A
TATA box-binding protein-associated factor RNA polymerase I subunit A is an enzyme that in humans is encoded by the TAF1A gene.[1][2]
# Function
Initiation of transcription by RNA polymerase I requires the formation of a complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs) specific for RNA polymerase I. This complex, known as SL1, binds to the core promoter of ribosomal RNA genes to position the polymerase properly and acts as a channel for regulatory signals. This gene encodes the smallest SL1-specific TAF. Two transcripts encoding different isoforms have been identified.[2]
# Interactions
TAF1A has been shown to interact with Acidic leucine-rich nuclear phosphoprotein 32 family member A[3] and Protein SET.[3] | https://www.wikidoc.org/index.php/TAF1A | |
275213cfd412db14c8f1b8444994fd66f7f14af0 | wikidoc | TAF5L | TAF5L
TAF5-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 5L is an enzyme that in humans is encoded by the TAF5L gene.
# Function
The product of this gene belongs to the WD-repeat TAF5 family of proteins. This gene encodes a protein that is a component of the PCAF histone acetylase complex. The PCAF histone acetylase complex, which is composed of more than 20 polypeptides some of which are TAFs, is required for myogenic transcription and differentiation. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors to facilitate complex assembly and transcription initiation. The encoded protein is structurally similar to one of the histone-like TAFs, TAF5. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.
# Interactions
TAF5L has been shown to interact with TAF9 and Transcription initiation protein SPT3 homolog. | TAF5L
TAF5-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 5L is an enzyme that in humans is encoded by the TAF5L gene.[1][2][3]
# Function
The product of this gene belongs to the WD-repeat TAF5 family of proteins. This gene encodes a protein that is a component of the PCAF histone acetylase complex. The PCAF histone acetylase complex, which is composed of more than 20 polypeptides some of which are TAFs, is required for myogenic transcription and differentiation. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors to facilitate complex assembly and transcription initiation. The encoded protein is structurally similar to one of the histone-like TAFs, TAF5. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene.[3]
# Interactions
TAF5L has been shown to interact with TAF9[4] and Transcription initiation protein SPT3 homolog.[4] | https://www.wikidoc.org/index.php/TAF5L | |
622dfc09c46bfad000c86c3c15d179c40eb8bd4f | wikidoc | TAF6L | TAF6L
TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L is an enzyme that in humans is encoded by the TAF6L gene.
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a protein that is a component of the PCAF histone acetylase complex and structurally similar to one of the histone-like TAFs, TAF6. The PCAF histone acetylase complex, which is composed of more than 20 polypeptides some of which are TAFs, is required for myogenic transcription and differentiation.
# Interactions
TAF6L has been shown to interact with TAF9 and Transcription initiation protein SPT3 homolog. | TAF6L
TAF6-like RNA polymerase II p300/CBP-associated factor-associated factor 65 kDa subunit 6L is an enzyme that in humans is encoded by the TAF6L gene.[1][2]
# Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes a protein that is a component of the PCAF histone acetylase complex and structurally similar to one of the histone-like TAFs, TAF6. The PCAF histone acetylase complex, which is composed of more than 20 polypeptides some of which are TAFs, is required for myogenic transcription and differentiation.[2]
# Interactions
TAF6L has been shown to interact with TAF9[3] and Transcription initiation protein SPT3 homolog.[3] | https://www.wikidoc.org/index.php/TAF6L | |
4572b9d350e77cb924deb9dfef401fb6ccb906d6 | wikidoc | TAF7l | TAF7l
TATA-box binding protein associated factor 7-like also known as CT40 is a protein that in humans is encoded by the TAF7l gene. It is a close homologue to the TAF7 gene, although its function may be different. Currently, little is known about this gene. It was originally demonstrated to be a testis-specific gene based on RT-PCR experiments on tissue extracts, however, it has now been found in white and brown adipose tissue, as well as in certain types of cancer.
# Function
## Function in Adipose Tissue Formation
Studies conducted on knockout animals have revealed that Taf7l makes important contributions in determining the fate of mesenchymal stem cells. Importantly, Zhou et al. found that in Taf7L−/− (Taf7L knockout)animals have decreased fat pads that are infiltrated by skeletal muscle tissue. Using RNA-seq and Gene Ontology Enrichment (GO), this same group found that there was an increase in GO terms (and thus gene categories) that werew involved in skeletal and muscle development. Combined with in vitro evidence, it appears that Taf7l is capable of initiating brown fat (the so-called healthy fat) production. Additionally, they found that together with PPARgamma, Taf7l likely can regulate the binding of the TFIID/RNA Polymerase II (RNAP II) complex. Specifically, the presence of Taf7l may alter chromatin looping and thus the association of distal enhancer sequences to BAT specific gene promoters, like Cidea and Scd1.
## Function in Cancer
Recently, frameshift mutation was found to be present in 3 patients with colorectal cancer. Specifically, a poly-A mono-nucleotide repeat region in Exon 6 of Taf7l was found to be missing one nucleotide (deletion mutation), resulting in a frameshift mutation. It has additionally been found to be decreased in 58% of Acute Myelogenous Leukemai (AML).
## Function in spermatogenesis: Reciprocity with TAF7
Much of the initial work came from Pointud et al. They found that Taf7l has dual functionality during spermatogenesis. In early stage spermatocytes, for example in primary spermatocytes (still diploid at this point), TAF7l is located in the cytoplasm, while TATA-binding protein (TBP) complex is located in the nucleus. Then, TAF7l slowly transitions to the nucleus during the mid-stage pachytene cell, where there is also a dramatic increase in TBP protein expression in the nucleus as well. Additionally, there is a reciprocal relationship to that of TAF7 expression: Unlike TAF7l, TAF7 at early stages is expressed in the nucleus, and thus separated from TAF7l. Then, at later stages, when TAF7l transitions into the nucleus, which happens around the time when the somatic (diploid) to germ cell (haploid) transition occurs, TAF7 dramatically declines. This may indicate that TAF7l plays an important role in regulating the TFIID during development of the sperm. Pointud et al. (2003) speculate that TAF7l may "bookmark" certain genes for expression or repression in the haploid spermatocyte.
## Function during Transcription
A definitive role for TAF7l during transcription still remains elusive. Yeast-2-hybrid screens have identified that TAF7l strongly interacts with TAF1 in exactly the same region (amino acids 1170-1226 of TAF1) that TAF7 binds to and inactivates TAF1's acetyltransferase (AT) function. Thus, it is likely that TAF7l shares a similar role to TAF7, in inhibiting TAF1 and thus, the activity of the TFIID complex. TAF7l localizes in a different compartment relative to TBP during early spermatogenesis, implying a TBP-independent function that awaits further study. Additionally, Chromosome Conformation Capture, has identified a role of TAF7 in directly mediating binding of enhancer elements to promoter sequences that TFIID binds to. This further suggests that TAF7l replaces the function of TAF7, as TAF7 has also been demonstrated to bind to and regulate gene (Vitamin D3 or Thyroid Hormone, for example) expression in a promoter specific fashion
- G. S. Gupta (2 Jul 2006). Proteomics of Spermatogenesis. Springer Science & Business Media. p. 327. ISBN 9780387276557..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} | TAF7l
TATA-box binding protein associated factor 7-like also known as CT40 is a protein that in humans is encoded by the TAF7l gene.[1] It is a close homologue to the TAF7 gene, although its function may be different. Currently, little is known about this gene. It was originally demonstrated to be a testis-specific gene based on RT-PCR experiments on tissue extracts,[1] however, it has now been found in white and brown adipose tissue,[2] as well as in certain types of cancer.[3]
# Function
## Function in Adipose Tissue Formation
Studies conducted on knockout animals have revealed that Taf7l makes important contributions in determining the fate of mesenchymal stem cells. Importantly, Zhou et al.[2] found that in Taf7L−/− (Taf7L knockout)animals have decreased fat pads that are infiltrated by skeletal muscle tissue. Using RNA-seq and Gene Ontology Enrichment (GO), this same group found that there was an increase in GO terms (and thus gene categories) that werew involved in skeletal and muscle development. Combined with in vitro evidence, it appears that Taf7l is capable of initiating brown fat (the so-called healthy fat) production. Additionally, they found that together with PPARgamma, Taf7l likely can regulate the binding of the TFIID/RNA Polymerase II (RNAP II) complex. Specifically, the presence of Taf7l may alter chromatin looping and thus the association of distal enhancer sequences to BAT specific gene promoters, like Cidea and Scd1.
## Function in Cancer
Recently, frameshift mutation was found to be present in 3 patients with colorectal cancer.[3] Specifically, a poly-A mono-nucleotide repeat region in Exon 6 of Taf7l was found to be missing one nucleotide (deletion mutation), resulting in a frameshift mutation. It has additionally been found to be decreased in 58% of Acute Myelogenous Leukemai (AML).
## Function in spermatogenesis: Reciprocity with TAF7
Much of the initial work came from Pointud et al.[1] They found that Taf7l has dual functionality during spermatogenesis. In early stage spermatocytes, for example in primary spermatocytes (still diploid at this point), TAF7l is located in the cytoplasm, while TATA-binding protein (TBP) complex is located in the nucleus. Then, TAF7l slowly transitions to the nucleus during the mid-stage pachytene cell, where there is also a dramatic increase in TBP protein expression in the nucleus as well. Additionally, there is a reciprocal relationship to that of TAF7 expression: Unlike TAF7l, TAF7 at early stages is expressed in the nucleus, and thus separated from TAF7l. Then, at later stages, when TAF7l transitions into the nucleus, which happens around the time when the somatic (diploid) to germ cell (haploid) transition occurs, TAF7 dramatically declines. This may indicate that TAF7l plays an important role in regulating the TFIID during development of the sperm. Pointud et al. (2003) speculate that TAF7l may "bookmark" certain genes for expression or repression in the haploid spermatocyte.
## Function during Transcription
A definitive role for TAF7l during transcription still remains elusive. Yeast-2-hybrid screens have identified that TAF7l strongly interacts with TAF1 in exactly the same region (amino acids 1170-1226 of TAF1) that TAF7 binds to and inactivates TAF1's acetyltransferase (AT) function.[1] Thus, it is likely that TAF7l shares a similar role to TAF7, in inhibiting TAF1 and thus, the activity of the TFIID complex. TAF7l localizes in a different compartment relative to TBP during early spermatogenesis, implying a TBP-independent function that awaits further study. Additionally, Chromosome Conformation Capture, has identified a role of TAF7 in directly mediating binding of enhancer elements to promoter sequences that TFIID binds to.[2] This further suggests that TAF7l replaces the function of TAF7, as TAF7 has also been demonstrated to bind to and regulate gene (Vitamin D3 or Thyroid Hormone, for example) expression in a promoter specific fashion [1]
- G. S. Gupta (2 Jul 2006). Proteomics of Spermatogenesis. Springer Science & Business Media. p. 327. ISBN 9780387276557..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/TAF7l | |
93f685e313752c3c44d4f4884665085058ee97e9 | wikidoc | TASP1 | TASP1
Threonine aspartase 1 is an enzyme that in humans is encoded by the TASP1 gene.
# Function
This gene encodes an endopeptidase that cleaves specific substrates following aspartate residues. The encoded protein undergoes posttranslational autoproteolytic processing to generate alpha and beta subunits, which reassemble into the active alpha2-beta2 heterotetramer. It is required to cleave MLL, a protein required for the maintenance of HOX gene expression, and TFIIA, a basal transcription factor. Cleavage of TFIIA has been found to drive spermatogenesis.
Alternatively spliced transcript variants have been described, but their biological validity has not been determined.
# Clinical significance
Taspase1 is overexpressed in primary human cancers and functions as a non-oncogene addiction protease that coordinates cancer cell proliferation and apoptosis. Therefore, Taspase1 may serve as a novel anti-cancer therapeutic target. | TASP1
Threonine aspartase 1 is an enzyme that in humans is encoded by the TASP1 gene.[1][2]
# Function
This gene encodes an endopeptidase that cleaves specific substrates following aspartate residues. The encoded protein undergoes posttranslational autoproteolytic processing to generate alpha and beta subunits, which reassemble into the active alpha2-beta2 heterotetramer. It is required to cleave MLL, a protein required for the maintenance of HOX gene expression, and TFIIA, a basal transcription factor. Cleavage of TFIIA has been found to drive spermatogenesis.[3]
Alternatively spliced transcript variants have been described, but their biological validity has not been determined.[2]
# Clinical significance
Taspase1 is overexpressed in primary human cancers and functions as a non-oncogene addiction protease that coordinates cancer cell proliferation and apoptosis. Therefore, Taspase1 may serve as a novel anti-cancer therapeutic target.[4] | https://www.wikidoc.org/index.php/TASP1 | |
b0a7cead8eb3bcf1332b1ef5cedbb3ca4886c1bb | wikidoc | TBRG4 | TBRG4
Transforming growth factor beta regulator 4 (TBRG4), also known as cell cycle progression restoration protein 2 (CPR2) and FAST kinase domain-containing protein 4 (FASTKD4), is a protein that in humans is encoded by the TBRG4 gene on chromosome 7. This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress and cell cycle progression. TBRG4 is involved in cell proliferation in hematopoiesis and multiple myeloma.
# Structure
TBRG4 shares structural characteristics of the FASTKD family, including an N-terminal mitochondrial targeting domain and three C-terminal domains: two FAST kinase-like domains (FAST_1 and FAST_2) and a RNA-binding domain (RAP). The mitochondrial targeting domain directs TBRG4 to be imported into the mitochondria. Though the functions of the C-terminal domains are unknown, RAP possibly binds RNA during trans-splicing. TBRG4 also contains multiple putative leucine zipper domains.
# Function
As a member of the FASTKD family, TBRG4 localizes to the mitochondria to modulate their energy balance, especially under conditions of stress. Though ubiquitously expressed in all tissues, TBRG4 appears more abundantly in skeletal muscle, heart muscle, and other tissues enriched in mitochondria. TBRG4 also localizes to the bone marrow (BM), where it functions in hematopoiesis by inducing IL-6 and VEGF secretion, which then stimulate cell proliferation and angiogenesis. However, it inhibits immunoglobulin secretions by normal B cells.
# Clinical significance
The involvement of TBRG4 in hematopoiesis links it to multiple myeloma (MM), which stems from malignant proliferation of plasma cells in the bone marrow. High expression of TBRG4 has been linked to enhanced cell proliferation and poorer outcome; thus, downregulation of its expression may contribute to reducing tumor growth by arresting cell cycle progression. | TBRG4
Transforming growth factor beta regulator 4 (TBRG4), also known as cell cycle progression restoration protein 2 (CPR2) and FAST kinase domain-containing protein 4 (FASTKD4), is a protein that in humans is encoded by the TBRG4 gene on chromosome 7.[1][2][3] This protein is part of the FASTKD family, which is known for regulating the energy balance of mitochondria under stress and cell cycle progression.[4][5] TBRG4 is involved in cell proliferation in hematopoiesis and multiple myeloma.[6][7]
# Structure
TBRG4 shares structural characteristics of the FASTKD family, including an N-terminal mitochondrial targeting domain and three C-terminal domains: two FAST kinase-like domains (FAST_1 and FAST_2) and a RNA-binding domain (RAP).[4][5] The mitochondrial targeting domain directs TBRG4 to be imported into the mitochondria. Though the functions of the C-terminal domains are unknown, RAP possibly binds RNA during trans-splicing.[4] TBRG4 also contains multiple putative leucine zipper domains.[2]
# Function
As a member of the FASTKD family, TBRG4 localizes to the mitochondria to modulate their energy balance, especially under conditions of stress. Though ubiquitously expressed in all tissues, TBRG4 appears more abundantly in skeletal muscle, heart muscle, and other tissues enriched in mitochondria.[4] TBRG4 also localizes to the bone marrow (BM), where it functions in hematopoiesis by inducing IL-6 and VEGF secretion, which then stimulate cell proliferation and angiogenesis. However, it inhibits immunoglobulin secretions by normal B cells.[6]
# Clinical significance
The involvement of TBRG4 in hematopoiesis links it to multiple myeloma (MM), which stems from malignant proliferation of plasma cells in the bone marrow.[6] High expression of TBRG4 has been linked to enhanced cell proliferation and poorer outcome; thus, downregulation of its expression may contribute to reducing tumor growth by arresting cell cycle progression.[7] | https://www.wikidoc.org/index.php/TBRG4 | |
835d0c0e2cdbb45733532df1fa04f549861e8e24 | wikidoc | TBX15 | TBX15
T-box transcription factor TBX15 is protein that in humans is encoded by the TBX15 gene.
TBX15 is a transcription factor involved in many developmental processes. TBX15 is a member of the T-box 1 subfamily and has been mapped to Chromosome 3. TBX15 is important in the development of the skeletal system. it is mainly associated with the development of the limbs, spinal column, and head. In particular, TBX15 is shown to influence the development of the scapula or shoulder blade.
# Clinical significance
Mutations of the TBX15 gene can cause a disease called Cousin Syndrome. This disease is associated with short stature, head and facial deformities, and underdevelopment of the shoulder blade and pelvis. Candille et al. showed that TBX15 is also associated with a genetic mutation in mice called droopy ear. Droopy ear is a genetic mutation resulting in craniofacial malformations most notably ears in abnormal locations. Droopy ear is associated with a deletion of a portion of the TBX15 gene. Droopy ear is also associated with abnormal skin color characteristics in mice. This shows another effect of the TBX15 gene which is helping to establishment of dorsoventral patterning of skin/ fur color. | TBX15
T-box transcription factor TBX15 is protein that in humans is encoded by the TBX15 gene.
TBX15 is a transcription factor involved in many developmental processes. TBX15 is a member of the T-box 1 subfamily and has been mapped to Chromosome 3.[1] TBX15 is important in the development of the skeletal system. it is mainly associated with the development of the limbs, spinal column, and head. In particular, TBX15 is shown to influence the development of the scapula or shoulder blade.[2]
# Clinical significance
Mutations of the TBX15 gene can cause a disease called Cousin Syndrome. This disease is associated with short stature, head and facial deformities, and underdevelopment of the shoulder blade and pelvis.[3] Candille et al. showed that TBX15 is also associated with a genetic mutation in mice called droopy ear. Droopy ear is a genetic mutation resulting in craniofacial malformations most notably ears in abnormal locations. Droopy ear is associated with a deletion of a portion of the TBX15 gene. Droopy ear is also associated with abnormal skin color characteristics in mice. This shows another effect of the TBX15 gene which is helping to establishment of dorsoventral patterning of skin/ fur color.[4] | https://www.wikidoc.org/index.php/TBX15 | |
ffefed5a981eb49160bf2aa731022611c3327d21 | wikidoc | TBX19 | TBX19
T-box transcription factor TBX19 is a protein that in humans is encoded by the TBX19 gene.
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes.
This gene is the human ortholog of mouse Tbx19/Tpit gene. Studies in mouse show that Tpit protein is present only in the two pituitary pro-opiomelanocortin (POMC)-expressing lineages, the corticotrophs and melanotrophs.
The Tpit gene is responsible for a neonatal form of acth deficiency and hypocortisolism.
Mutations in the human ortholog were found in patients with isolated deficiency of pituitary POMC-derived ACTH, suggesting an essential role for this gene in differentiation of the pituitary POMC lineage. | TBX19
T-box transcription factor TBX19 is a protein that in humans is encoded by the TBX19 gene.[1]
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes.
This gene is the human ortholog of mouse Tbx19/Tpit gene. Studies in mouse show that Tpit protein is present only in the two pituitary pro-opiomelanocortin (POMC)-expressing lineages, the corticotrophs and melanotrophs.
The Tpit gene is responsible for a neonatal form of acth deficiency and hypocortisolism. [2]
Mutations in the human ortholog were found in patients with isolated deficiency of pituitary POMC-derived ACTH, suggesting an essential role for this gene in differentiation of the pituitary POMC lineage.[3] | https://www.wikidoc.org/index.php/TBX19 | |
946fa8a94c08d8d08300b8dc75a7ac8b04a3fa31 | wikidoc | TBX20 | TBX20
TBX20 (gene)
is a member of the T-box family that encodes the transcription factor TBX20. Studies in mouse, human and fruitfly have shown that this gene is essential for early heart development, adult heart function and yolk sac vasculature remodeling and has been associated with congenital heart diseases. Tbx20 was also shown to be required for migration of hindbrain motor neurons and in facial neurons was proposed to be a positive regulator of the non-canonical Wnt signaling pathway.
Tbx20 is a transcription factor that is essential for proper heart development in a growing fetus. Any mutations in this gene can result in various forms of congenital heart disease. One of the more serious examples is the presence of a septal defect. The interatrial septum is a piece of tissue that separates the left and right atria of the heart, which contain oxygenated and deoxygenated blood, respectively. In Tbx20 mutants, this divider does not form and results in deoxygenated blood flowing into the left atrium then left ventricle, which ships the blood to the organs and muscles. Since deoxygenated blood should not be delivered to the tissues, the result is cyanosis, or a bluish skin discoloration stemming from low oxygen concentration. Proper function of Tbx20 is essential because it controls other genes that regulate cardiomyocyte proliferation, such as Tbx2 and N-myc1. Cardiomyocytes are the basis for the correct architectural scheme of the heart, and if defects arise in these structures, proper heart development is likely unattainable.
# Embryonic heart functions
Tbx20 knockout mouse embryos die at around or before E10.5 with hypoplastic hearts.
This gene has been implicated in coordinating cardiac proliferation, regional specification and formation of the cardiac chamber Congenital heart diseases involving TBX20 include defects in septation, chamber growth and valvulogenesis and increased Tbx20 expression was shown to cause congenital atrial septal defects, patent foramen ovale and cardiac valve defects.
# Adult heart functions
In the fruitfly, knock-down of nmr (neuromancer), Drosophila's Tbx20 homolog gene, led to slower heart rate, arrythmias and abnormal myofibrillar architecture. Heterozygous Tbx20 knockout adult mice displayed left ventricle dilation, decreased wall thickness and contractile abnormalities.
Homozygous conditional cardiomyocyte Tbx20 knockout adult mice died within 15 days after knockout induction. Mice hearts presented with dilated cardiomyopathy and contraction-related dysfunctions such as abnormal atrioventricular conduction, slower heart rate, altered ventricular depolarization/repolarization and arrhythmias.
# Known co-factors
Transcription factors GATA4 and NKX2-5 have been shown to physically interact with TBX20 and enhance gene expression.
# Known downstream gene targets
Tbx2 was shown to be directly repressed by Tbx20 in the myocardium. Analysis of data from genome-wide chromatin immunoprecipitation against TBX20 tagged with green fluorescent protein in adult (6–8 weeks) mouse whole heart, coupled with analysis of genes differentially expressed upon loss of Tbx20, identified hundreds of putative TBX20 direct targets. | TBX20
TBX20 (gene)
is a member of the T-box family that encodes the transcription factor TBX20. Studies in mouse, human and fruitfly have shown that this gene is essential for early heart development,[1][2][3][4] adult heart function[5] and yolk sac vasculature remodeling[3] and has been associated with congenital heart diseases.[6][7][8] Tbx20 was also shown to be required for migration of hindbrain motor neurons and in facial neurons was proposed to be a positive regulator of the non-canonical Wnt signaling pathway.
Tbx20 is a transcription factor that is essential for proper heart development in a growing fetus. Any mutations in this gene can result in various forms of congenital heart disease. One of the more serious examples is the presence of a septal defect. The interatrial septum is a piece of tissue that separates the left and right atria of the heart, which contain oxygenated and deoxygenated blood, respectively. In Tbx20 mutants, this divider does not form and results in deoxygenated blood flowing into the left atrium then left ventricle, which ships the blood to the organs and muscles. Since deoxygenated blood should not be delivered to the tissues, the result is cyanosis, or a bluish skin discoloration stemming from low oxygen concentration. Proper function of Tbx20 is essential because it controls other genes that regulate cardiomyocyte proliferation, such as Tbx2 and N-myc1. Cardiomyocytes are the basis for the correct architectural scheme of the heart, and if defects arise in these structures, proper heart development is likely unattainable.[9]
# Embryonic heart functions
Tbx20 knockout mouse embryos die at around or before E10.5 with hypoplastic hearts.[1][2][3][4]
This gene has been implicated in coordinating cardiac proliferation, regional specification[1] and formation of the cardiac chamber[2][3][4] Congenital heart diseases involving TBX20 include defects in septation, chamber growth and valvulogenesis[6][7] and increased Tbx20 expression was shown to cause congenital atrial septal defects, patent foramen ovale and cardiac valve defects.[8]
# Adult heart functions
In the fruitfly, knock-down of nmr (neuromancer), Drosophila's Tbx20 homolog gene, led to slower heart rate, arrythmias and abnormal myofibrillar architecture.[5] Heterozygous Tbx20 knockout adult mice displayed left ventricle dilation, decreased wall thickness and contractile abnormalities.[3]
Homozygous conditional cardiomyocyte Tbx20 knockout adult mice died within 15 days after knockout induction. Mice hearts presented with dilated cardiomyopathy and contraction-related dysfunctions such as abnormal atrioventricular conduction, slower heart rate, altered ventricular depolarization/repolarization and arrhythmias.[10]
# Known co-factors
Transcription factors GATA4 and NKX2-5 have been shown to physically interact with TBX20 and enhance gene expression.[3]
# Known downstream gene targets
Tbx2 was shown to be directly repressed by Tbx20 in the myocardium.[1][3] Analysis of data from genome-wide chromatin immunoprecipitation against TBX20 tagged with green fluorescent protein in adult (6–8 weeks) mouse whole heart, coupled with analysis of genes differentially expressed upon loss of Tbx20, identified hundreds of putative TBX20 direct targets.[10][11] | https://www.wikidoc.org/index.php/TBX20 | |
6a9a0b2b811edca8f56de60caf53a5cc4d2e82f3 | wikidoc | TBX21 | TBX21
T-box transcription factor TBX21 is a protein that in humans is encoded by the TBX21 gene.
# Function
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells.
# Role in disease
## Asthma
The transcription factor encoded by TBX21 is T-bet, which regulates the development of naive T lymphocytes. Asthma is a disease of chronic inflammation, and it is known that transgenic mice born without TBX21 spontaneously develop abnormal lung function consistent with asthma. It is thought that TBX21, therefore, may play a role in the development of asthma in humans as well. | TBX21
T-box transcription factor TBX21 is a protein that in humans is encoded by the TBX21 gene.[1]
# Function
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is the human ortholog of mouse Tbx21/Tbet gene. Studies in mouse show that Tbx21 protein is a Th1 cell-specific transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (IFNG). Expression of the human ortholog also correlates with IFNG expression in Th1 and natural killer cells, suggesting a role for this gene in initiating Th1 lineage development from naive Th precursor cells.[1]
# Role in disease
## Asthma
The transcription factor encoded by TBX21 is T-bet, which regulates the development of naive T lymphocytes. Asthma is a disease of chronic inflammation, and it is known that transgenic mice born without TBX21 spontaneously develop abnormal lung function consistent with asthma. It is thought that TBX21, therefore, may play a role in the development of asthma in humans as well.[2] | https://www.wikidoc.org/index.php/TBX21 | |
e1347ef223139a394a90d133f3a1fee163212670 | wikidoc | TBX22 | TBX22
T-box transcription factor TBX22 is a protein that in humans is encoded by the TBX22 gene.
TBX22 is a member of a phylogenetically conserved family of proteins that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, cleft palate with ankyloglossia (tongue-tie), and it is believed to play a major role in human palatogenesis. It has previously been mapped to the long arm of the X chromosome and it has now been demonstrated that mutations in the gene TBX22 are the cause of this syndrome. TBX22 mutations also result in non-syndromic cleft palate in some populations.
TBX22 is composed of seven exons spanning 8.7 kilobases of genomic DNA in Xq21.1. The TBX22 mRNA is 2099 base pairs long and encodes a 400-amino-acids protein containing a T-domain in its NH2-terminal region which has the unique feature of missing 20 amino-acids relative to the other known T-domains.
# Function
T-box genes are members of a family of transcriptional regulators that contain a region encoding a conserved DNA-binding motif of approximately 200 amino acids: the T-domain. These genes are grouped together on the basis of the homology existing between their products and the mouse Brachyury (or T) protein. In human and mouse, numerous T-domain-containing genes have been identified so far and mapped throughout the genome. The spatio-temporal expression of these genes is strictly regulated during the development of both vertebrates and invertebrates.
Functional studies have demonstrated that several T-box genes are involved in mesoderm specification in the developing embryo of mouse or Xenopus. In mice, the Brachyury gene is expressed in early mesoderm cells and its expression then becomes restricted to the notochord. The Brachyury protein binds as a dimer to a 20-nucleotide partially palindromic sequence recognized by its T-domain. More generally, T-box genes have been shown to be critical during development for proper morphogenesis and organogenesis. Abnormal expression of several T-box genes has been shown to cause developmental anomalies in mouse, Drosophila or zebrafish.
# Clinical significance
In humans, two T-box genes are involved in inherited disorders: mutations in TBX5 cause Holt–Oram syndrome, whereas mutations in TBX3 cause ulnar–mammary syndrome.
Mutations in TBX22 cause X-linked cleft palate and ankyloglossia. CPX has been described in a small number of families exhibiting a strong X linked Mendelian inheritance. The cleft phenotype predominantly affects males who show variation ranging from a complete cleft of the secondary palate, submucous cleft, or bifid uvula to high arched palate. Ankyloglossia is frequently seen in affected patients and carrier females, and has proved to be a useful indicator of CPX. Temporal and spatial studies using in situ hybridization in both human and mouse has shown that TBX22/Tbx22 is expressed primarily in the palatal shelves and tongue during palatogenesis, indicating a specific role of TBX22 in both palatal and tongue development. In addition to families with well defined X linked inheritance, TBX22 mutations have been identified in several families where pedigree size and/or family history were too limited to predict mode of inheritance. In these cases, ascertainment was largely based on the presence of ankyloglossia as well as cleft palate.
It has been demonstrated that TBX22 makes a significant contribution to the prevalence of cleft palate at least in the Brazilian and the North American cohorts. To date, 10 different TBX22 mutations have been reported in patients with CP and/or ankyloglossia. These include small deletions/insertions, nonsense, splice site, frameshift and missense alterations. | TBX22
T-box transcription factor TBX22 is a protein that in humans is encoded by the TBX22 gene.[1]
TBX22 is a member of a phylogenetically conserved family of proteins that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene have been associated with the inherited X-linked disorder, cleft palate with ankyloglossia (tongue-tie), and it is believed to play a major role in human palatogenesis.[1] It has previously been mapped to the long arm of the X chromosome and it has now been demonstrated that mutations in the gene TBX22 are the cause of this syndrome.[2] TBX22 mutations also result in non-syndromic cleft palate in some populations.[3]
TBX22 is composed of seven exons spanning 8.7 kilobases of genomic DNA in Xq21.1. The TBX22 mRNA is 2099 base pairs long and encodes a 400-amino-acids protein containing a T-domain in its NH2-terminal region which has the unique feature of missing 20 amino-acids relative to the other known T-domains.[4]
# Function
T-box genes are members of a family of transcriptional regulators that contain a region encoding a conserved DNA-binding motif of approximately 200 amino acids: the T-domain. These genes are grouped together on the basis of the homology existing between their products and the mouse Brachyury (or T) protein. In human and mouse, numerous T-domain-containing genes have been identified so far and mapped throughout the genome. The spatio-temporal expression of these genes is strictly regulated during the development of both vertebrates and invertebrates.[4]
Functional studies have demonstrated that several T-box genes are involved in mesoderm specification in the developing embryo of mouse or Xenopus. In mice, the Brachyury gene is expressed in early mesoderm cells and its expression then becomes restricted to the notochord. The Brachyury protein binds as a dimer to a 20-nucleotide partially palindromic sequence recognized by its T-domain. More generally, T-box genes have been shown to be critical during development for proper morphogenesis and organogenesis. Abnormal expression of several T-box genes has been shown to cause developmental anomalies in mouse, Drosophila or zebrafish.
# Clinical significance
In humans, two T-box genes are involved in inherited disorders: mutations in TBX5 cause Holt–Oram syndrome, whereas mutations in TBX3 cause ulnar–mammary syndrome.[4]
Mutations in TBX22 cause X-linked cleft palate and ankyloglossia.[5] CPX has been described in a small number of families exhibiting a strong X linked Mendelian inheritance. The cleft phenotype predominantly affects males who show variation ranging from a complete cleft of the secondary palate, submucous cleft, or bifid uvula to high arched palate. Ankyloglossia is frequently seen in affected patients and carrier females, and has proved to be a useful indicator of CPX. Temporal and spatial studies using in situ hybridization in both human and mouse has shown that TBX22/Tbx22 is expressed primarily in the palatal shelves and tongue during palatogenesis, indicating a specific role of TBX22 in both palatal and tongue development. In addition to families with well defined X linked inheritance, TBX22 mutations have been identified in several families where pedigree size and/or family history were too limited to predict mode of inheritance. In these cases, ascertainment was largely based on the presence of ankyloglossia as well as cleft palate.[6]
It has been demonstrated that TBX22 makes a significant contribution to the prevalence of cleft palate at least in the Brazilian and the North American cohorts.[4] To date, 10 different TBX22 mutations have been reported in patients with CP and/or ankyloglossia.[7] These include small deletions/insertions, nonsense, splice site, frameshift and missense alterations.[3] | https://www.wikidoc.org/index.php/TBX22 | |
668e5bcdc7d490930a640c96324aa4d07c15b17f | wikidoc | TCAIM | TCAIM
TCAIM is a protein that in humans is encoded by the TCAIM gene (T-cell activation inhibitor, mitochondrial).
# Gene
The gene is located on chromosome 3, at position 3p21.31, and is 71,333 bases long. A graphic of the image is show below in Fig.1.2 The TCAIM protein is 496 residues long and weighs 57925 Da. It exists in four different isoforms. TCAIM is highly conserved among different species, but no homologies to protein families of known functions were discovered.
## Transcript
There are 8 alternatively spliced exons, which encode 4 transcript variants. The primary transcript, which is 3520 bp, is well conserved among orthologs, with the human isoform 1 having high identity with orthologous proteins. The X1 transcript contauns 11 exons, which yield a polypeptide that is 496 amino acid residues in length.
# Protein
## General properties
The isoelectric point is significantly greater than average for human proteins (6.81).
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is composed mostly of long alpha-helices with several coil regions and strands dispersed throughout the length of the protein. The ends of the protein consist of coil regions opposite the N- and C- terminal ends.
## Expression
TCAIM is moderately expressed (50-75%) in most tissues in the body. However, a study on NCBI GEO discussing the effect of disease states on TCAIM mRNA expression found that protein expression was actually elevated in HPV positive tissues compared to the HPV negative tissues. Another study found that TCAIM expression was elevated in individuals with Type 2 diabetes and insulin resistance. The expression of TCAIM seems to be contingent on the specific disease state in a variety of cases.
## Subcellular localization
The protein contains a mitochondrial signal peptide localizing it to the mitochondrial matrix. Analysis via the EXPASY localization software confirmed this finding. The high isoelectric point of the Human protein provides further evidence for the mitochondrial localization due to the high pH of the mitochondrial matrix.
## Post-translational modifications
### Cleavage sites
The protein is initially cleaved to remove the 26 amino acids from the N-terminus. This represents a signal peptide after it is localized to the mitochondrion.
### Phosphorylation
There are a number of predicted phosphorylation sites, as see in the figure to the right. Serine residues are more likely to undergo phosphorylation than threonine or tyrosine residues.
### O-linked glycosylation
Shown to the right are a number of predicted o-linked sites. None have been experimentally determined thus far.
# Homology and Evolution
## Homologs
An alignment of Homo sapiens TCAIM and Danio rerio (Zebrafish) homologs was performed using the SDSC workbench. There is approximately 55% identity between the two orthologs, with a global alignment score of 1817. The two orthologs are consistently similar throughout the entirety of their sequences. The differences between the two genes is due seemingly random segments of non-conserved and semiconserved residues scattered throughout the two alignments. This difference may be due to the non-relatedness between the two organisms.
## Evolutionary history
TCAIM diverged much quicker than cytochrome C, but slightly slower than fibrinogen.
# Function
Not much is known about the function; it is surmised that this protein may play a role in apoptosis of T-cells. TCAIM may play a role in the innate immune signaling via the mitochondria.
# Clinical significance
A research study was performed by Vogel et al. They previously found that TCAIM is highly expressed in grafts and tissues of tolerance-developing transplant patients and that the protein is localized in the mitochondria. In this study, they found that TCAIM interacts with and is regulated by CD11c(+) dendritic cells. Another article by Hendrikson et. el briefly mentions TCAIM. They found that genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression. The third article is another research that finds evidence that TCAIM (along with mitochondrial genes) could be used as a marker in patients to predict whether they could accept an allograft or reject it. | TCAIM
TCAIM is a protein that in humans is encoded by the TCAIM gene[1][2] (T-cell activation inhibitor, mitochondrial).
# Gene
The gene is located on chromosome 3, at position 3p21.31, and is 71,333 bases long. A graphic of the image is show below in Fig.1.2 The TCAIM protein is 496 residues long and weighs 57925 Da. It exists in four different isoforms. TCAIM is highly conserved among different species, but no homologies to protein families of known functions were discovered.[3]
## Transcript
There are 8 alternatively spliced exons, which encode 4 transcript variants. The primary transcript, which is 3520 bp, is well conserved among orthologs, with the human isoform 1 having high identity with orthologous proteins. The X1 transcript contauns 11 exons, which yield a polypeptide that is 496 amino acid residues in length.[4]
# Protein
## General properties
The isoelectric point is significantly greater than average for human proteins (6.81).[5]
## Structure
Shown to the right is a predicted tertiary structure of the protein. It is composed mostly of long alpha-helices with several coil regions and strands dispersed throughout the length of the protein. The ends of the protein consist of coil regions opposite the N- and C- terminal ends.
## Expression
TCAIM is moderately expressed (50-75%) in most tissues in the body.[7] However, a study on NCBI GEO discussing the effect of disease states on TCAIM mRNA expression found that protein expression was actually elevated in HPV positive tissues compared to the HPV negative tissues. Another study found that TCAIM expression was elevated in individuals with Type 2 diabetes and insulin resistance. The expression of TCAIM seems to be contingent on the specific disease state in a variety of cases.[8]
## Subcellular localization
The protein contains a mitochondrial signal peptide localizing it to the mitochondrial matrix.[9] Analysis via the EXPASY localization software[10] confirmed this finding. The high isoelectric point of the Human protein provides further evidence for the mitochondrial localization due to the high pH of the mitochondrial matrix.
## Post-translational modifications
### Cleavage sites
The protein is initially cleaved to remove the 26 amino acids from the N-terminus. This represents a signal peptide after it is localized to the mitochondrion.[9]
### Phosphorylation
There are a number of predicted phosphorylation sites, as see in the figure to the right. Serine residues are more likely to undergo phosphorylation than threonine or tyrosine residues.
### O-linked glycosylation
Shown to the right are a number of predicted o-linked sites. None have been experimentally determined thus far.[when?]
# Homology and Evolution
## Homologs
An alignment of Homo sapiens TCAIM and Danio rerio (Zebrafish) homologs was performed using the SDSC workbench. There is approximately 55% identity between the two orthologs, with a global alignment score of 1817. The two orthologs are consistently similar throughout the entirety of their sequences. The differences between the two genes is due seemingly random segments of non-conserved and semiconserved residues scattered throughout the two alignments. This difference may be due to the non-relatedness between the two organisms.[13]
## Evolutionary history
TCAIM diverged much quicker than cytochrome C, but slightly slower than fibrinogen.[14]
# Function
Not much is known about the function; it is surmised that this protein may play a role in apoptosis of T-cells. TCAIM may play a role in the innate immune signaling via the mitochondria.[15]
# Clinical significance
A research study was performed by Vogel et al. They previously found that TCAIM is highly expressed in grafts and tissues of tolerance-developing transplant patients and that the protein is localized in the mitochondria. In this study, they found that TCAIM interacts with and is regulated by CD11c(+) dendritic cells.[15] Another article by Hendrikson et. el briefly mentions TCAIM. They found that genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression.[3] The third article is another research that finds evidence that TCAIM (along with mitochondrial genes) could be used as a marker in patients to predict whether they could accept an allograft or reject it.[16] | https://www.wikidoc.org/index.php/TCAIM | |
aa4b4469d70fc20d8e98bd772fed3220c97c28ec | wikidoc | TCF12 | TCF12
Transcription factor 12 is a protein that in humans is encoded by the TCF12 gene.
The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH) E-protein family that recognizes the consensus binding site (E-box) CANNTG. This encoded protein is expressed in many tissues, among them skeletal muscle, thymus, B- and T-cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.
Mutations in this gene have been associated to cases of coronal craniosynostosis (doi: 10.1038/ng.2531) | TCF12
Transcription factor 12 is a protein that in humans is encoded by the TCF12 gene.[1][2]
The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH) E-protein family that recognizes the consensus binding site (E-box) CANNTG. This encoded protein is expressed in many tissues, among them skeletal muscle, thymus, B- and T-cells, and may participate in regulating lineage-specific gene expression through the formation of heterodimers with other bHLH E-proteins. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.[2]
Mutations in this gene have been associated to cases of coronal craniosynostosis (doi: 10.1038/ng.2531) | https://www.wikidoc.org/index.php/TCF12 | |
37ceb06780801a7989f7306186b5f93c8c734f89 | wikidoc | TDRD7 | TDRD7
Tudor domain-containing protein 7 is a protein that in humans is encoded by the TDRD7 gene.
In melanocytic cells TDRD7 gene expression may be regulated by MITF.
# Gene polymorphism
Various single nucleotide polymorphisms (SNPs) of the TDRD7 gene have been identified and for some of them an association with lower susceptibility to age-related cataract was shown.
# Interactions
TDRD7 has been shown to interact with TACC1. | TDRD7
Tudor domain-containing protein 7 is a protein that in humans is encoded by the TDRD7 gene.[1][2]
In melanocytic cells TDRD7 gene expression may be regulated by MITF.[3]
# Gene polymorphism
Various single nucleotide polymorphisms (SNPs) of the TDRD7 gene have been identified and for some of them an association with lower susceptibility to age-related cataract was shown.[4]
# Interactions
TDRD7 has been shown to interact with TACC1.[5] | https://www.wikidoc.org/index.php/TDRD7 | |
1cab6613412afe376d1394df09efad46402ad94b | wikidoc | TEAD1 | TEAD1
Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene. TEAD1 was the first member of the TEAD family of transcription factors to be identified.
# Structure
All members of the TEAD family share a highly conserved DNA binding domain called the TEA domain. This DNA binding domain has a consensus DNA sequence 5’-CATTCCA/T-3’ that is called the MCAT element. The three dimensional structure of the TEA domain has been identified . Its conformation is close to that of the homeodomain and contains 3 α helixes (H1, H2 and H3). It is the H3 helix that enables TEAD proteins to bind DNA.
Another conserved domain of TEAD1 is located at the C terminus of the protein. It allows the binding of cofactors and has been called the YAP1 binding domain, because it is its ability to bind this well-known TEAD proteins co-factor that led to its identification. Indeed, TEAD proteins cannot induce gene expression on their own. They have to associate with cofactors to be able to act
# Tissue distribution
TEAD1 is expressed in various tissues including skeletal muscle, pancreas, placenta, lung, and heart.
# Orthologs
TEAD proteins are found in many organisms under different names, assuming different functions. For example, in Saccharomyces cerevisiae TEC-1 regulates the transposable element TY1 and is involved in pseudohyphale growth (the elongated shape that yeasts take when grown in nutrient-poor conditions). In Aspergillus nidulans, the TEA domain protein ABAA regulates the differentiation of conidiophores. In drosophila the transcription factor Scalloped is involved in the development of the wing disc, survival and cell growth. Finally in Xenopus it has been demonstrated that the ortholog of TEAD1 regulates muscle differentiation.
# Function
- Heart development (myocardium differentiation,
- Skeletal muscle development (alpha-actin of skeletal muscles),)
- Smooth muscle development (alpha-actin of smooth muscles),
- Regulation of myosin heavy chain genes, cardiac muscular genes troponin T and I
- Regulation of proliferation,
- Regulation of apoptosis,
# Post-transcriptional modifications
Protein Kinase A (pKA) can phosphorylate TEAD1 at serine 102, after the TEA domain. This phosphorylation is needed for the transcriptional activation of the α MyHC gene. Protein Kinase C (pKC) phosphorylates TEAD1 on serine and threonine next to the last alpha loop in the TEA domain. This phosphorylation decreases TEAD1 binding to the GTIIC enhancer.
TEAD1 can be palmitoylated on a conserved cysteine at the C-term of the protein. This post-translational modification is critical for proper folding of TEAD proteins and their stability.
# Cofactors
TEAD proteins require cofactors to induce the transcription of target genes. TEAD1 interacts with all members of the SRC family of steroid receptor coactivators. In HeLa cells TEAD1 and SRC induce gene expression, TEAD1 interacts with PARP (Poly-ADP ribose polymerase) to regulate smooth muscle α-actin expression. PARP can also ADP-ribosylate the TEAD proteins and make the chromatin context favorable to transcription through histone modification, SRF (Serum response factor) and TEAD1 together regulate gene expression.
TEAD proteins and MEF2 (myocyte enhancer factor 2) interact physically. The binding of MEF2 on DNA induces and potentiates TEAD1 recruitment at MCAT sequences that are adjacent to MEF2 binding sites. This recruitment leads to the repression of the MLC2v (Myosin Light Chain 2 v) and βMHC ( β-myosin heavy chain ) promoter. TEAD1 and the phosphoprotein MAX interact in vivo and in vitro. Once this complex is formed, these two proteins can regulate the alpha-myosin heavy chain (α-MHC) gene expression.
The four Vestigial-like (VGLL) proteins are able to interact with all TEADs. The precise function of TEAD and VGLL interaction is still poorly understood. It has been shown that TEAD/VGLL1 complexes promote anchorage-independent cell proliferation in prostate cancer cell lines suggesting a role in cancer progression Moreover, VGLL2 interaction with TEAD1 activates muscle promoter upon C2C12 differentiation and enhances MyoD-mediated myogenic in 10T1/2. Finally the complex TEAD/VGLL4 acts as a default transcriptional repressor.
The interaction between YAP (Yes Associated Protein 65), TAZ, a transcriptional coactivator paralog to YAP, and all TEAD proteins was demonstrated both in vitro and in vivo. In both cases the interaction of the proteins leads to increased TEAD transcriptional activity. YAP/TAZ are effectors of the Hippo tumor suppressor pathway that restricts organ growth by keeping in check cell proliferation and promoting apoptosis in mammals and also in Drosophila.
# Role in cancer
Analysis of cancer transcriptome databases (www.ebi.ac.uk/gxa) showed that TEAD1 is dysregulated in several types of cancers. First in Kaposi sarcoma there is a 300-fold increase in TEAD1 levels. Moreover, the increase of TEAD expression can be detected in basal-like breast cancers, fallopian tube carcinoma, and germ cell tumors. Otherwise, in other types of cancer TEAD expression is decreased, for example in other breast cancer types and in renal or bladder cancers. This dual role can be explained by the different targets and the differential regulation of target genes by TEAD transcription factors. Finally recent studies showed that TEAD1 and YAP in ovarian cancer can induces cell stemness and chemoresistance. and that genetic variant of TEAD protein and YAP are enriched in some cancers. | TEAD1
Transcriptional enhancer factor TEF-1 also known as TEA domain family member 1 (TEAD1) and transcription factor 13 (TCF-13) is a protein that in humans is encoded by the TEAD1 gene.[1][2][3][4] TEAD1 was the first member of the TEAD family of transcription factors to be identified.[1][5]
# Structure
All members of the TEAD family share a highly conserved DNA binding domain called the TEA domain.[6] This DNA binding domain has a consensus DNA sequence 5’-CATTCCA/T-3’ that is called the MCAT element.[7] The three dimensional structure of the TEA domain has been identified [5]. Its conformation is close to that of the homeodomain and contains 3 α helixes (H1, H2 and H3). It is the H3 helix that enables TEAD proteins to bind DNA.[8]
Another conserved domain of TEAD1 is located at the C terminus of the protein. It allows the binding of cofactors and has been called the YAP1 binding domain, because it is its ability to bind this well-known TEAD proteins co-factor that led to its identification. Indeed, TEAD proteins cannot induce gene expression on their own. They have to associate with cofactors to be able to act[9]
# Tissue distribution
TEAD1 is expressed in various tissues including skeletal muscle, pancreas, placenta, lung, and heart.[10][11][12][13][14][15][16]
# Orthologs
TEAD proteins are found in many organisms under different names, assuming different functions. For example, in Saccharomyces cerevisiae TEC-1 regulates the transposable element TY1 and is involved in pseudohyphale growth (the elongated shape that yeasts take when grown in nutrient-poor conditions).[17] In Aspergillus nidulans, the TEA domain protein ABAA regulates the differentiation of conidiophores.[18] In drosophila the transcription factor Scalloped is involved in the development of the wing disc, survival and cell growth.[19] Finally in Xenopus it has been demonstrated that the ortholog of TEAD1 regulates muscle differentiation.[20]
# Function
- Heart development (myocardium differentiation,[21]
- Skeletal muscle development (alpha-actin of skeletal muscles),[22][23][24])
- Smooth muscle development (alpha-actin of smooth muscles),[22][25]
- Regulation of myosin heavy chain genes,[26] cardiac muscular genes troponin T and I [5]
- Regulation of proliferation,[27][28][29]
- Regulation of apoptosis,[30][31]
# Post-transcriptional modifications
Protein Kinase A (pKA) can phosphorylate TEAD1 at serine 102, after the TEA domain. This phosphorylation is needed for the transcriptional activation of the α MyHC gene.[32] Protein Kinase C (pKC) phosphorylates TEAD1 on serine and threonine next to the last alpha loop in the TEA domain. This phosphorylation decreases TEAD1 binding to the GTIIC enhancer.[33]
TEAD1 can be palmitoylated on a conserved cysteine at the C-term of the protein. This post-translational modification is critical for proper folding of TEAD proteins and their stability.[34]
# Cofactors
TEAD proteins require cofactors to induce the transcription of target genes.[10] TEAD1 interacts with all members of the SRC family of steroid receptor coactivators. In HeLa cells TEAD1 and SRC induce gene expression,[35] TEAD1 interacts with PARP (Poly-ADP ribose polymerase) to regulate smooth muscle α-actin expression. PARP can also ADP-ribosylate the TEAD proteins and make the chromatin context favorable to transcription through histone modification,[36] SRF (Serum response factor) and TEAD1 together regulate gene expression.[37]
TEAD proteins and MEF2 (myocyte enhancer factor 2) interact physically. The binding of MEF2 on DNA induces and potentiates TEAD1 recruitment at MCAT sequences that are adjacent to MEF2 binding sites. This recruitment leads to the repression of the MLC2v (Myosin Light Chain 2 v) and βMHC ( β-myosin heavy chain ) promoter.[38] TEAD1 and the phosphoprotein MAX interact in vivo and in vitro. Once this complex is formed, these two proteins can regulate the alpha-myosin heavy chain (α-MHC) gene expression.[39]
The four Vestigial-like (VGLL) proteins are able to interact with all TEADs.[40] The precise function of TEAD and VGLL interaction is still poorly understood. It has been shown that TEAD/VGLL1 complexes promote anchorage-independent cell proliferation in prostate cancer cell lines suggesting a role in cancer progression [41] Moreover, VGLL2 interaction with TEAD1 activates muscle promoter upon C2C12 differentiation and enhances MyoD-mediated myogenic in 10T1/2.[42] Finally the complex TEAD/VGLL4 acts as a default transcriptional repressor.[43]
The interaction between YAP (Yes Associated Protein 65), TAZ, a transcriptional coactivator paralog to YAP, and all TEAD proteins was demonstrated both in vitro and in vivo. In both cases the interaction of the proteins leads to increased TEAD transcriptional activity.[43][44] YAP/TAZ are effectors of the Hippo tumor suppressor pathway that restricts organ growth by keeping in check cell proliferation and promoting apoptosis in mammals and also in Drosophila.[27][45]
# Role in cancer
Analysis of cancer transcriptome databases (www.ebi.ac.uk/gxa) showed that TEAD1 is dysregulated in several types of cancers. First in Kaposi sarcoma there is a 300-fold increase in TEAD1 levels. Moreover, the increase of TEAD expression can be detected in basal-like breast cancers,[46][47] fallopian tube carcinoma,[48] and germ cell tumors.[49] Otherwise, in other types of cancer TEAD expression is decreased, for example in other breast cancer types and in renal or bladder cancers. This dual role can be explained by the different targets and the differential regulation of target genes by TEAD transcription factors.[31][50] Finally recent studies showed that TEAD1 and YAP in ovarian cancer can induces cell stemness and chemoresistance.[51] and that genetic variant of TEAD protein and YAP are enriched in some cancers.[52] | https://www.wikidoc.org/index.php/TEAD1 | |
d06676032d0cac3d899dcb0bf9207ff37fae8945 | wikidoc | TEAD2 | TEAD2
TEAD2 (ETF, ETEF-1, TEF-4), together with TEAD1, defined a novel family of transcription factors, the TEAD family, highly conserved through evolution.
TEAD proteins were notably found in Drosophila (Scalloped), C. elegans (egl -44), S. cerevisiae and A. nidulans.
TEAD2 has been less studied than TEAD1 but a few studies revealed its role during development.
# Function
TEAD2 is a member of the mammalian TEAD transcription factor family (initially named the transcriptional enhancer factor (TEF) family), which contain the TEA/ATTS DNA-binding domain. Members of the family in mammals are TEAD1, TEAD2, TEAD3, TEAD4.
# Tissue distribution
TEAD2 is selectively expressed in a subset of embryonic tissues including the cerebellum, testis, and distal portions of the forelimb and hindlimb buds, as well as the tail bud, but it is essentially absent from adult tissues. TEAD2 has also been shown to be expressed very early during development, i.e. from the 2-cell stage.
# TEAD orthologs
TEAD proteins are found in many organisms under different names, assuming different functions.
For example, in Saccharomyces cerevisiae TEC-1 regulates the transposable element TY1 and is involved in pseudohyphale growth (the elongated shape that yeasts take when grown in nutrient-poor conditions).
In Aspergillus nidulans, the TEA domain protein ABAA regulates the differentiation of conidiophores.
In drosophila the transcription factor Scalloped is involved in the development of the wing disc, survival and cell growth.
Finally in Xenopus, it has been demonstrated that the homolog of TEAD regulates muscle differentiation.
# Function
- Regulation of mouse neural development
- Neuron proliferation
- Regulation of proliferation
- Regulation of apoptosis
# Post transcriptional modifications
TEAD1 can be palmitoylated on a conserved cysteine at the C-term of the protein. This post-translational modification is critical for proper folding of TEAD proteins and their stability.
Based on bioinformatics evidence TEAD2 can be ubiquitinylated at Lys75 and several phosphorylation sites exist in the protein.
# Cofactors
TEAD transcription factors have to associate with cofactors to be able to induce the transcription of target genes. Concerning TEAD2 very few studies have shown specific cofactors. But due the high homology between the TEAD family members its believed that TEAD proteins may share cofactors. Here are presented the cofactor that interact with TEAD2.
- TEAD2 interacts with all members of the SRC family of steroid receptor coactivators. It has been shown in HeLa cells that TEAD2 and SRC induce gene expression.
- SRF (Serum response factor) and TEAD2 interact through their DNA binding domain, respectively the MADS domain and the TEA domain. In vitro studies demonstrated that this interaction leads to the activation of the skeletal muscle α-actin promoter.
- TEAD proteins and MEF2 (myocyte enhancer factor 2) interact physically. The binding of MEF2 on the DNA induces and potentiates TEAD2 recruitment at MCAT sequences that are adjacent to MEF2 binding sites.
- The four Vestigial-like (VGLL) proteins are able to interact with all TEADs. The precise function of TEAD and VGLL interaction is still poorly understood. It has been shown that TEAD/VGLL1 complexes promote anchorage-independent cell proliferation in prostate cancer cell lines suggesting a role in cancer progression.
- The interaction between YAP (Yes Associated Protein 65), TAZ, a transcriptional coactivator paralog to YAP, and all TEAD proteins was demonstrated both in vitro and in vivo. In both cases the interaction of the proteins leads to increased TEAD transcriptional activity. YAP/TAZ are effectors of the Hippo tumor suppressor pathway that restricts organ growth by keeping in check cell proliferation and promoting apoptosis in mammals and also in Drosophila.
# Clinical significance
Recent animal models indicating a possible association of TEAD2 with anencephaly. | TEAD2
TEAD2 (ETF, ETEF-1, TEF-4), together with TEAD1, defined a novel family of transcription factors, the TEAD family, highly conserved through evolution.[1][2]
TEAD proteins were notably found in Drosophila (Scalloped), C. elegans (egl -44), S. cerevisiae and A. nidulans.
TEAD2 has been less studied than TEAD1 but a few studies revealed its role during development.
# Function
TEAD2 is a member of the mammalian TEAD transcription factor family (initially named the transcriptional enhancer factor (TEF) family), which contain the TEA/ATTS DNA-binding domain.[3] Members of the family in mammals are TEAD1, TEAD2, TEAD3, TEAD4.
# Tissue distribution
TEAD2 is selectively expressed in a subset of embryonic tissues including the cerebellum, testis, and distal portions of the forelimb and hindlimb buds, as well as the tail bud, but it is essentially absent from adult tissues.[4] TEAD2 has also been shown to be expressed very early during development, i.e. from the 2-cell stage.[5]
# TEAD orthologs
TEAD proteins are found in many organisms under different names, assuming different functions.
For example, in Saccharomyces cerevisiae TEC-1 regulates the transposable element TY1 and is involved in pseudohyphale growth (the elongated shape that yeasts take when grown in nutrient-poor conditions).[6]
In Aspergillus nidulans, the TEA domain protein ABAA regulates the differentiation of conidiophores.[7]
In drosophila the transcription factor Scalloped is involved in the development of the wing disc, survival and cell growth.[8]
Finally in Xenopus, it has been demonstrated that the homolog of TEAD regulates muscle differentiation.[9]
# Function
- Regulation of mouse neural development[10]
- Neuron proliferation[11]
- Regulation of proliferation[12]
- Regulation of apoptosis[13]
# Post transcriptional modifications
TEAD1 can be palmitoylated on a conserved cysteine at the C-term of the protein. This post-translational modification is critical for proper folding of TEAD proteins and their stability.[14]
Based on bioinformatics evidence TEAD2 can be ubiquitinylated at Lys75 and several phosphorylation sites exist in the protein.
# Cofactors
TEAD transcription factors have to associate with cofactors to be able to induce the transcription of target genes.[15] Concerning TEAD2 very few studies have shown specific cofactors. But due the high homology between the TEAD family members its believed that TEAD proteins may share cofactors. Here are presented the cofactor that interact with TEAD2.
- TEAD2 interacts with all members of the SRC family of steroid receptor coactivators. It has been shown in HeLa cells that TEAD2 and SRC induce gene expression.[16]
- SRF (Serum response factor) and TEAD2 interact through their DNA binding domain, respectively the MADS domain and the TEA domain. In vitro studies demonstrated that this interaction leads to the activation of the skeletal muscle α-actin promoter.[17]
- TEAD proteins and MEF2 (myocyte enhancer factor 2) interact physically. The binding of MEF2 on the DNA induces and potentiates TEAD2 recruitment at MCAT sequences that are adjacent to MEF2 binding sites.[18]
- The four Vestigial-like (VGLL) proteins are able to interact with all TEADs.[19] The precise function of TEAD and VGLL interaction is still poorly understood. It has been shown that TEAD/VGLL1 complexes promote anchorage-independent cell proliferation in prostate cancer cell lines suggesting a role in cancer progression.[20]
- The interaction between YAP (Yes Associated Protein 65), TAZ, a transcriptional coactivator paralog to YAP, and all TEAD proteins was demonstrated both in vitro and in vivo. In both cases the interaction of the proteins leads to increased TEAD transcriptional activity.[21][22] YAP/TAZ are effectors of the Hippo tumor suppressor pathway that restricts organ growth by keeping in check cell proliferation and promoting apoptosis in mammals and also in Drosophila.[23][24]
# Clinical significance
Recent animal models indicating a possible association of TEAD2 with anencephaly.[25] | https://www.wikidoc.org/index.php/TEAD2 | |
3b3a8da14f09bb6f9d117109898d702230b5af74 | wikidoc | TENC1 | TENC1
Tensin-like C1 domain-containing phosphatase is an enzyme that in humans is encoded by the TENC1 gene.
The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and participates in signaling pathways. This protein plays a role in regulating cell migration. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified.
# Interactions
TENC1 has been shown to interact with AXL receptor tyrosine kinase. | TENC1
Tensin-like C1 domain-containing phosphatase is an enzyme that in humans is encoded by the TENC1 gene.[1]
The protein encoded by this gene belongs to the tensin family. Tensin is a focal adhesion molecule that binds to actin filaments and participates in signaling pathways. This protein plays a role in regulating cell migration. Alternative splicing occurs at this locus and three transcript variants encoding three distinct isoforms have been identified.[1]
# Interactions
TENC1 has been shown to interact with AXL receptor tyrosine kinase.[2] | https://www.wikidoc.org/index.php/TENC1 | |
04966e66da6abae03bd4dbec73f403a389af353d | wikidoc | TENM3 | TENM3
Teneurin-3, also known as Ten-m3, Odz3, Ten-m/Odz3, Tenascin-like molecule major 3 or Teneurin transmembrane protein 3, is a protein that, in humans, is encoded by the TENM3, or ODZ3, gene. Ten-m3 is a ~300 kDa type II transmembrane glycoprotein that is a member of the teneurin/Ten-m/Odz family. The teneurin family currently consists of four members: Ten-m1-Ten-m4. Ten-ms are conserved across both vertebrate and invertebrate species. They are expressed in distinct, but often interconnected, areas of the developing nervous system and in some non-neural tissues. Like the Ten-m family, Ten-m3 plays a critical role in regulating connectivity of the nervous system, particularly in axon pathfinding and synaptic organisation in the motor and visual system. Mutation in the TENM3/ODZ3 gene in humans has been associated with the eye condition, microphthalmia.
# History
Teneurin protein was first identified and characterised in Drosophila by Baumgartner and Chiquet-Ehrismann in early 1990s. They were looking for the invertebrate homologue of the extracellular matrix glycoprotein tenascin-C to learn more about its structure and function. The embryonic Drosophila cDNA library was screened using polymerase chain reaction (PCR) and a primer derived from the EGF-like repeats region of chicken tenascin-C protein. Two novel molecules containing similar tenascin-like repeats were identified, which were named Ten-a for “tenascin-like molecule accessory” and Ten-m for “tenascin-like molecule major”. Around the same time, Levine et al. also identified Ten-m in Drosophila by screening for tyrosine phosphorylation on cDNA using monoclonal antibodies. However, they named this gene odd Oz (Odz) after the oddless pair-rule phenotype displayed in Odz mutant embryos, where every odd-numbered body segment was deleted.
Since discovery of teneurins in Drosophila, many other laboratories have independently described the Ten-a and Ten-m/Odz homolog proteins in different vertebrates. However, various names were assigned to these vertebrate homologs, which complicated the nomenclature of teneurin proteins. The proteins were called Ten-ms in zebrafish, teneurins in chicken, Ten-m1-4, Odz1-4, Ten-m/Odz1-4, DOC4 in mouse, neurestin in rat, and teneurin or Odz in human.
The name teneurin was coined by Minet et al. in 1999 from the original name, Ten-a, and the major site of the protein expression being in the nervous system.
# Structure
Like the Ten-m family, Ten-m3 is a large type II transmembrane glycoprotein that has a molecular weight of ~300 kDa and is composed of ~2800 amino acids. Teneurins are highly conserved within and between species. The primary structure, or amino acid sequence identity, of the proteins between paralogs is ~60% identical and between orthologs is ~90%, whilst between vertebrates and Drosophila or C. elegans is only 33-41% identical.
All teneurins, especially in mouse, are type II transmembrane proteins that are composed of a large extracellular C terminal domain of ~2400 amino acid residues, a single transmembrane helical domain of ~30 hydrophobic residues and an intracellular N terminal domain of ~300-375 residues. The extracellular domain of the molecule can undergo dimerisation.
## Extracellular domain
The extracellular C terminal domain is composed of a linker region, EGF-like repeats and then a globular domain. The linker region is made up of ~200 amino acid residues and is found immediately distal to the transmembrane domain. This is followed by eight phylogenetically conserved tenascin C-type EGF-like repeats, which features the uniquely conserved replacement of a single cysteine in repeats 2 and 5 in place of the original tyrosine and phenylalanine residues respectively. Since cysteines are susceptible to forming disulfide bonds, the single cysteines at the EGF-like repeats of a teneurin molecule can facilitate the homophilic and heterophilic dimerisation of teneurin family molecules.
More distally is the globular domain consisting of a 700-800 amino acid residue region. There are 17 conserved cysteine residues, a region of NHL repeats, a region of 26 YD residue repeats, and then a teneurin C-associated peptide (TCAP). The YD repeats are rich in N-linked glycosylation and were previously only reported in the rhs element of bacteria.
The TCAP is the resulting peptide from cleaving a putative furin cleavage site found immediately on the N-terminal of TCAP. The furin cleavage site is rich in tyrosine residues and consists of 4 conserved cysteine residues. The 4 cysteine residues assist in protein folding, however, they are absent in Ten-m2 and Ten-m3. There are 41 amino acids in TCAPs, except for TCAP-3 from Ten-m3, which has 40. TCAPs show structural homology to the CRF family molecule and appears to influence neurite outgrowth and some behaviours relating to stress and anxiety.
## Intracellular domain
The N terminal intracellular domain (ICD) consists of two proline-rich regions in the half closest to the transmembrane domain, two EF-hand-like motifs near the centre, and a number of conserved tyrosine phosphorylation sites. The proline-rich stretches are typical binding sites for SH3 proteins, which can regulate intracellular teneurin signalling pathway.
# Interactions
Teneurins are homophilic adhesion molecules that bind specifically to other teneurin-family molecules on adjacent cells. The NHL domain on the extracellular domain of teneurins acts as a homophilic recognition site to mediate this specific binding. This interaction facilitates neurite outgrowth and the adhesion strength needed to stop outgrowth. The dimerisation of the extracellular domains of teneurin molecules can lead to the proteolytic cleavage of the ICD. A weak nuclear localisation signal in the ICD of Ten-m3 facilitates the translocation of the ICD into the nucleus.
TCAPs from the extracellular domain of a teneurin molecule can form an intercellular adhesive complex when bound to the adhesion family G-protein coupled receptor latrophilin, which is involved in gamete migration and gonadal morphology.
# Expression
Teneurin molecules are prominently expressed in distinctive, but often overlapping, populations of neurons, especially during embryonic development. They are also expressed in some non-neuronal tissues that regulate pattern formation and sites of cell migration. Some Ten-m3 expressions can occur in a high-to-low gradient.
## Embryonic expression
At day 7.5 in mouse embryonic development (E7.5), in situ hybridisation shows Ten-m3 mRNA expression at the neural plate, particularly in the neural folds. At E8.5, Ten-m3 is expressed at the caudal forebrain, the midbrain region and structures outside of the CNS, including the pharyngeal arches and the otic vesicles. At E9.5 and 10.5, Ten-m3 expression extends from the telencephalon to the midbrain and also at the pharyngeal arches, otic vesicles, anterior somites and the limb buds. Between these stages, Ten-m3 and Ten-m4 are expressed in complementary patterns in the brain, suggesting a complementary function during development. At E12.5, Ten-m3 is higher in the midbrain compared to the caudal diencephalon and the spinal cord. It is also co-expressed with Ten-m4 in the first, second and third pharyngeal arches. At E15.5, Ten-m3 is expressed in the forebrain and facial mesenchyme, but absent from the mid- and hindbrain. It is also expressed in the developing whisker pads in mouse.
## Adult expression
In a 6-week old adult mouse, Ten-m3 is co-expressed with the other three Ten-m mRNAs at the granular layer of the dentate gyrus and the stratum pyramidale of the hippocampus. It is expressed relatively weakly in the granular layer and in the stratum lacunosum moleculare, but is strongly expressed in the CA2 subfield and weakly in the CA1 subfield of the hippocampus. However, immunostaining of Ten-m3 shows weak protein expression throughout the hippocampus except for the stratum lacunosum moleculare. Ten-m3 mRNA is prominently co-expressed with Ten-m2 and Ten-m4 in the Purkinje’s cell zone of the cerebellum. Ten-m3 protein is expressed in the Purkinje’s cell zone, molecular and granular layers and the white matter of the cerebellum. All Ten-m mRNAs are expressed prominently between layers II and VI of the cerebrum.
## Gradient expression
The Ten-m3 gene, along with Ten-m2 and Ten-m4, is expressed throughout the neocortex in a low rostral to high caudal and a high dorsal-medial to low ventral-lateral gradient from E15.5 to P2. In E17 mouse, Ten-m3 mRNA is expressed in the parafascicular thalamic nucleus, a subregion of the thalamus, and in the striatum in a high dorsal-caudal to low ventral-rostral gradient. Patches of this expression can still be observed in first week postnatal mice. Similarly, there is a graded expression of Ten-m3 in the visual pathway, especially during embryonic and early postnatal development. Expression is highest in the dorsal lateral geniculate nucleus (dLGN) and superior colliculus in the region that corresponds topographically to ventral retina.
# Function
## Motor skill acquisition
Ten-m3 plays an important role during early development in directing the topographic neural projection and formation of the thalamostriatal circuitry, thus critical for motor skill acquisition. Ten-m3 molecule is the first to be reported to regulate connectivity in the thalamostriatal pathway. Ten-m3 guides some of the axon projections from dorsal regions of the parafascicular nucleus (PF) of the thalamus to dorsal regions of the striatum. This creates a high dorsal to low ventral gradient topography mapping between the two structures. In Ten-m3 null mutant mice, these projections are diffuse and project ectopically to more ventral and medial regions in the striatum. Furthermore, the null mutant mice display delayed motor skill acquisition in the accelerating rotorod task.
## Binocular vision
In in vivo vertebrate studies, Ten-m3 acts as an eye-specific guidance molecule during early development. Functional binocular vision requires the correct projection of ipsilateral axons from the retina to the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1) and to the superior colliculus (SC).
Ten-m3 facilitates the retinotopic mapping of ipsilateral axons from the ventrotemporal retinal ganglion cells, which encode visual input from the binocular visual field, to the dorsomedial dLGN and to the rostromedial SC. Immunostaining reveals a cluster of high Ten-m3 protein expression in the areas involved in this ipsilateral mapping. In Ten-m3 null mutant mice, these projections are reduced and ectopic projections are expanded ventrolaterally along the dLGN and caudomedially in the SC from both eyes. The aberrant misalignment of ipsilateral axons from both eyes result in binocular vision deficits. Ten-m3 null mutant mice performed worse than wild type (WT) in behavioural tests of binocular visual function, such as vertical placement and visual cliff test. However, inactivation of inputs from one eye (i.e. inactivate binocular vision) restored visual behaviour to a level similar to WT mice under binocular condition.
## Teneurin C-Associated Peptide functions
The peptide cleaved from the C terminal of Ten-m3, TCAP-3, stimulates the production of cAMP and the proliferation of neurons. It can increase the expression of its gene at high concentrations but attenuate the expression at low concentrations.
TCAP-1 from Ten-m1, another member of the Ten-m family, modulates stress and anxiety behaviours. TCAP-1 increases the acoustic startle response in a low-anxiety rat but decreases the response in a high anxiety rat when injected into the basolateral amygdala. It also inhibits the sensitisation of the response when injected into the lateral ventricles.
# Disease Linkage
A case study reports a family with autosomal recessive colobomatous microphthalmia in two children of third-cousin parents. This developmental condition results in small-sized eyes and is associated with coloboma. PCR analysis identified the homozygous null mutation to be in the ODZ3 gene, which is important for the early developing eye. | TENM3
Teneurin-3, also known as Ten-m3, Odz3, Ten-m/Odz3, Tenascin-like molecule major 3 or Teneurin transmembrane protein 3, is a protein that, in humans, is encoded by the TENM3, or ODZ3, gene.[1][2][3][4] Ten-m3 is a ~300 kDa type II transmembrane glycoprotein that is a member of the teneurin/Ten-m/Odz family. The teneurin family currently consists of four members: Ten-m1-Ten-m4. Ten-ms are conserved across both vertebrate and invertebrate species. They are expressed in distinct, but often interconnected, areas of the developing nervous system and in some non-neural tissues. Like the Ten-m family, Ten-m3 plays a critical role in regulating connectivity of the nervous system, particularly in axon pathfinding and synaptic organisation in the motor and visual system.[5][6] Mutation in the TENM3/ODZ3 gene in humans has been associated with the eye condition, microphthalmia.[7]
# History
Teneurin protein was first identified and characterised in Drosophila by Baumgartner and Chiquet-Ehrismann in early 1990s.[1] They were looking for the invertebrate homologue of the extracellular matrix glycoprotein tenascin-C to learn more about its structure and function. The embryonic Drosophila cDNA library was screened using polymerase chain reaction (PCR) and a primer derived from the EGF-like repeats region of chicken tenascin-C protein. Two novel molecules containing similar tenascin-like repeats were identified, which were named Ten-a for “tenascin-like molecule accessory” and Ten-m for “tenascin-like molecule major”.[1][5] Around the same time, Levine et al.[2] also identified Ten-m in Drosophila by screening for tyrosine phosphorylation on cDNA using monoclonal antibodies. However, they named this gene odd Oz (Odz) after the oddless pair-rule phenotype displayed in Odz mutant embryos, where every odd-numbered body segment was deleted.
Since discovery of teneurins in Drosophila, many other laboratories have independently described the Ten-a and Ten-m/Odz homolog proteins in different vertebrates. However, various names were assigned to these vertebrate homologs, which complicated the nomenclature of teneurin proteins.[5] The proteins were called Ten-ms in zebrafish,[8] teneurins in chicken,[9] Ten-m1-4, Odz1-4, Ten-m/Odz1-4, DOC4 in mouse,[10][11] neurestin in rat,[12] and teneurin or Odz in human.[13][3]
The name teneurin was coined by Minet et al. in 1999[3] from the original name, Ten-a, and the major site of the protein expression being in the nervous system.
# Structure
Like the Ten-m family, Ten-m3 is a large type II transmembrane glycoprotein that has a molecular weight of ~300 kDa and is composed of ~2800 amino acids. Teneurins are highly conserved within and between species. The primary structure, or amino acid sequence identity, of the proteins between paralogs is ~60% identical and between orthologs is ~90%, whilst between vertebrates and Drosophila or C. elegans is only 33-41% identical.[5]
All teneurins, especially in mouse, are type II transmembrane proteins that are composed of a large extracellular C terminal domain of ~2400 amino acid residues, a single transmembrane helical domain of ~30 hydrophobic residues and an intracellular N terminal domain of ~300-375 residues.[5] The extracellular domain of the molecule can undergo dimerisation.
## Extracellular domain
The extracellular C terminal domain is composed of a linker region, EGF-like repeats and then a globular domain. The linker region is made up of ~200 amino acid residues and is found immediately distal to the transmembrane domain. This is followed by eight phylogenetically conserved tenascin C-type EGF-like repeats, which features the uniquely conserved replacement of a single cysteine in repeats 2 and 5 in place of the original tyrosine and phenylalanine residues respectively. Since cysteines are susceptible to forming disulfide bonds, the single cysteines at the EGF-like repeats of a teneurin molecule can facilitate the homophilic and heterophilic dimerisation of teneurin family molecules.[10]
More distally is the globular domain consisting of a 700-800 amino acid residue region. There are 17 conserved cysteine residues, a region of NHL repeats, a region of 26 YD residue repeats, and then a teneurin C-associated peptide (TCAP). The YD repeats are rich in N-linked glycosylation and were previously only reported in the rhs element of bacteria.[15][16]
The TCAP is the resulting peptide from cleaving a putative furin cleavage site found immediately on the N-terminal of TCAP. The furin cleavage site is rich in tyrosine residues and consists of 4 conserved cysteine residues. The 4 cysteine residues assist in protein folding, however, they are absent in Ten-m2 and Ten-m3. There are 41 amino acids in TCAPs, except for TCAP-3 from Ten-m3, which has 40.[17] TCAPs show structural homology to the CRF family molecule and appears to influence neurite outgrowth and some behaviours relating to stress and anxiety.[5][6]
## Intracellular domain
The N terminal intracellular domain (ICD) consists of two proline-rich regions in the half closest to the transmembrane domain, two EF-hand-like motifs near the centre, and a number of conserved tyrosine phosphorylation sites. The proline-rich stretches are typical binding sites for SH3 proteins, which can regulate intracellular teneurin signalling pathway.[18]
# Interactions
Teneurins are homophilic adhesion molecules that bind specifically to other teneurin-family molecules on adjacent cells. The NHL domain on the extracellular domain of teneurins acts as a homophilic recognition site to mediate this specific binding. This interaction facilitates neurite outgrowth and the adhesion strength needed to stop outgrowth.[15] The dimerisation of the extracellular domains of teneurin molecules can lead to the proteolytic cleavage of the ICD. A weak nuclear localisation signal in the ICD of Ten-m3 facilitates the translocation of the ICD into the nucleus.[19][14]
TCAPs from the extracellular domain of a teneurin molecule can form an intercellular adhesive complex when bound to the adhesion family G-protein coupled receptor latrophilin, which is involved in gamete migration and gonadal morphology.[20]
# Expression
Teneurin molecules are prominently expressed in distinctive, but often overlapping, populations of neurons, especially during embryonic development. They are also expressed in some non-neuronal tissues that regulate pattern formation and sites of cell migration. Some Ten-m3 expressions can occur in a high-to-low gradient.[21][5]
## Embryonic expression
At day 7.5 in mouse embryonic development (E7.5), in situ hybridisation shows Ten-m3 mRNA expression at the neural plate, particularly in the neural folds. At E8.5, Ten-m3 is expressed at the caudal forebrain, the midbrain region and structures outside of the CNS, including the pharyngeal arches and the otic vesicles. At E9.5 and 10.5, Ten-m3 expression extends from the telencephalon to the midbrain and also at the pharyngeal arches, otic vesicles, anterior somites and the limb buds. Between these stages, Ten-m3 and Ten-m4 are expressed in complementary patterns in the brain, suggesting a complementary function during development. At E12.5, Ten-m3 is higher in the midbrain compared to the caudal diencephalon and the spinal cord. It is also co-expressed with Ten-m4 in the first, second and third pharyngeal arches. At E15.5, Ten-m3 is expressed in the forebrain and facial mesenchyme, but absent from the mid- and hindbrain. It is also expressed in the developing whisker pads in mouse.[8][21]
## Adult expression
In a 6-week old adult mouse, Ten-m3 is co-expressed with the other three Ten-m mRNAs at the granular layer of the dentate gyrus and the stratum pyramidale of the hippocampus. It is expressed relatively weakly in the granular layer and in the stratum lacunosum moleculare, but is strongly expressed in the CA2 subfield and weakly in the CA1 subfield of the hippocampus. However, immunostaining of Ten-m3 shows weak protein expression throughout the hippocampus except for the stratum lacunosum moleculare. Ten-m3 mRNA is prominently co-expressed with Ten-m2 and Ten-m4 in the Purkinje’s cell zone of the cerebellum. Ten-m3 protein is expressed in the Purkinje’s cell zone, molecular and granular layers and the white matter of the cerebellum. All Ten-m mRNAs are expressed prominently between layers II and VI of the cerebrum.[21]
## Gradient expression
The Ten-m3 gene, along with Ten-m2 and Ten-m4, is expressed throughout the neocortex in a low rostral to high caudal and a high dorsal-medial to low ventral-lateral gradient from E15.5 to P2.[22] In E17 mouse, Ten-m3 mRNA is expressed in the parafascicular thalamic nucleus, a subregion of the thalamus, and in the striatum in a high dorsal-caudal to low ventral-rostral gradient. Patches of this expression can still be observed in first week postnatal mice.[23][24] Similarly, there is a graded expression of Ten-m3 in the visual pathway, especially during embryonic and early postnatal development. Expression is highest in the dorsal lateral geniculate nucleus (dLGN) and superior colliculus in the region that corresponds topographically to ventral retina.[25][14]
# Function
## Motor skill acquisition
Ten-m3 plays an important role during early development in directing the topographic neural projection and formation of the thalamostriatal circuitry, thus critical for motor skill acquisition. Ten-m3 molecule is the first to be reported to regulate connectivity in the thalamostriatal pathway. Ten-m3 guides some of the axon projections from dorsal regions of the parafascicular nucleus (PF) of the thalamus to dorsal regions of the striatum. This creates a high dorsal to low ventral gradient topography mapping between the two structures. In Ten-m3 null mutant mice, these projections are diffuse and project ectopically to more ventral and medial regions in the striatum. Furthermore, the null mutant mice display delayed motor skill acquisition in the accelerating rotorod task.[24]
## Binocular vision
In in vivo vertebrate studies, Ten-m3 acts as an eye-specific guidance molecule during early development. Functional binocular vision requires the correct projection of ipsilateral axons from the retina to the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1) and to the superior colliculus (SC).
Ten-m3 facilitates the retinotopic mapping of ipsilateral axons from the ventrotemporal retinal ganglion cells, which encode visual input from the binocular visual field, to the dorsomedial dLGN and to the rostromedial SC. Immunostaining reveals a cluster of high Ten-m3 protein expression in the areas involved in this ipsilateral mapping. In Ten-m3 null mutant mice, these projections are reduced and ectopic projections are expanded ventrolaterally along the dLGN and caudomedially in the SC from both eyes. The aberrant misalignment of ipsilateral axons from both eyes result in binocular vision deficits. Ten-m3 null mutant mice performed worse than wild type (WT) in behavioural tests of binocular visual function, such as vertical placement and visual cliff test. However, inactivation of inputs from one eye (i.e. inactivate binocular vision) restored visual behaviour to a level similar to WT mice under binocular condition.[25][14]
## Teneurin C-Associated Peptide functions
The peptide cleaved from the C terminal of Ten-m3, TCAP-3, stimulates the production of cAMP and the proliferation of neurons. It can increase the expression of its gene at high concentrations but attenuate the expression at low concentrations.[17]
TCAP-1 from Ten-m1, another member of the Ten-m family, modulates stress and anxiety behaviours. TCAP-1 increases the acoustic startle response in a low-anxiety rat but decreases the response in a high anxiety rat when injected into the basolateral amygdala. It also inhibits the sensitisation of the response when injected into the lateral ventricles.[26]
# Disease Linkage
A case study reports a family with autosomal recessive colobomatous microphthalmia in two children of third-cousin parents. This developmental condition results in small-sized eyes and is associated with coloboma. PCR analysis identified the homozygous null mutation to be in the ODZ3 gene, which is important for the early developing eye.[7] | https://www.wikidoc.org/index.php/TENM3 | |
6cf4c0a8c80e8ff4ddb1ebc182c9e1f8b528a29d | wikidoc | TERF1 | TERF1
Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.
# Gene
The human TERF1 gene is located in the chromosome 8 at 73,921,097-73,960,357 bp. Two transcripts of this gene are alternatively spliced products. The TERF1 gene is also known as TRF, PIN2 (Proteinase Inhibitor 2), TRF1, t-TRF1 and h-TRF1-AS.
# Protein
The protein structure contains a C-terminal Myb motif, a dimerization domain near its N-terminus and an acidic N-terminus.
# Subcellular distribution
The cellular composition of this DNA binding protein features the nucleoplasm, chromosomes, a telomeric region, a nuclear telomere cap complex, the cytoplasm, the spindle, the nucleus and a nucleolus and a nuclear chromosome.
# Function
# Inhibitor telomerase
TERF 1 gene encodes a telomere specific protein which is a component of the telomere nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. It is known to protect telomeres in mammals from DNA mechanisms that are used for repair purposes and at the same time regulate the activity carried out by telomerase. The telomeric repeat binding factor 1 protein is present at telomeres, where the cells aging aspect is monitored, throughout the typical cell cycle process. The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1) is a protein that binds at telomere ends.
This gene encodes a telomere specific protein which is a component of the shelterin nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. The protein has the ultimate use of functioning as an inhibitor of telomerase, a protein enzyme that assists in the elongation of chromosomes by the addition of sequences of TTAGGG to the end of the chromosomes. The protein acts as cis-regulatory elements in the process of limiting the ends of individual chromosomes from elongating as facilitated by telomerase and the TTAGGG sequences. The structure of the protein consists of a dimerization domain close to its Amino terminus, a Carboxyl terminal tail, which is the free carboxyl group that terminates the end of a protein chain and an acidic Amino terminus, which is the free amine group that terminates the start of a protein.
# Biological processes
The protein is also actively involved in biological processes such as the response to drug and the negative regulation of the maintenance of telomere through the process of semi-conservative replication, similar to that of cis. In addition, according to Kaplan and Christopher, the protein is also involved in the biological processes of positive regulation of the polymerization of the microtubule and negative control of the process of DNA replication. This protein is also useful in the biological process of mitosis and the positive regulation of mitosis. It positively regulates the mitotic cell cycle. The protein encoded by the TERF 1 gene is also involved in the biological process of cell division and the negative regulation of the maintenance of telomere facilitated by the enzyme telomerase.
Other than functioning as an inhibitor of the enzyme telomerase in the process of elongation of the ends of chromosomes, the protein has other functions. These functions include the binding of the protein, facilitation in the activity of protein homodimerization, the binding of DNA and facilitation in the activity of protein heterodimerization as well as the binding of the microtubule. Additionally, the protein has a molecular function of binding telomeric DNA and the double-stranded telomeric DNA. The telomeric repeat-binding factor 1 protein is also used in the binding of chromatin and the whole activity of bending of the DNA.
# TERF 1 protein levels correlates with telomere length in colorectal cancer
Telomeres protect the chromosome from degradation by nucleases and end-to-end fusion. The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1) is a protein that binds at telomere ends.
To measure the concentrations of TRF1 and the relationships among telomere length, telomerase activity, and TRF1 levels in tumor and normal colorectal mucosa, from normal and tumoral samples of patients who underwent surgery for colorectal cancer we analyzed TRF1 protein concentration, and telomerase activity were analysed.
As result high levels of TRF1 were observed in 68.7% of tumor samples, while the majority of normal samples showed negative or weak TRF1 concentrations. Among the tumor samples, telomere length was significantly associated with TRF1 protein levels.
In conclusion a relationship exists between telomere length and TRF1 abundance protein in tumor samples, which means that TRF1 is an important factor in the tumor progression and maybe a diagnostic factor.
# Interactions
The TERF1 encoded protein has been shown to have interactions with the following; SALL1 (Sal-like1- Drosophila, a protein.), ABL (Abelson murine leukemia viral oncogene homolog, a protein), MAPRE2 (Microtubule-associated protein RP/EB, a protein), ATM (Ataxia telangiectasia mutated, a protein kinase), PINX1 (TERF1-interacting telomerase inhibitor 1), TINF2 (TERF1-interacting telomerase nuclear factor), TNKS2 (Tankyrase, an enzyme) and NME1 (nucleoside diphosphate kinase).In conclusion, as mentioned above, the telomeric repeat-binding factor 1 protein has most of its functions related to the binding of components and regulation of processes.
TERF1 has been shown to interact with:
- Abl gene,
- Ataxia telangiectasia mutated,
- MAPRE1,
- NME1,
- PINX1
- SALL1,
- TINF2,
- TNKS2, and
- TNKS. | TERF1
Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.[1][2]
# Gene
The human TERF1 gene is located in the chromosome 8 at 73,921,097-73,960,357 bp. Two transcripts of this gene are alternatively spliced products.[2] The TERF1 gene is also known as TRF, PIN2 (Proteinase Inhibitor 2), TRF1, t-TRF1 and h-TRF1-AS.[3]
# Protein
The protein structure contains a C-terminal Myb motif, a dimerization domain near its N-terminus and an acidic N-terminus.
# Subcellular distribution
The cellular composition of this DNA binding protein features the nucleoplasm, chromosomes, a telomeric region, a nuclear telomere cap complex, the cytoplasm, the spindle, the nucleus and a nucleolus and a nuclear chromosome.
# Function
# Inhibitor telomerase
TERF 1 gene encodes a telomere specific protein which is a component of the telomere nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. It is known to protect telomeres in mammals from DNA mechanisms that are used for repair purposes and at the same time regulate the activity carried out by telomerase. The telomeric repeat binding factor 1 protein is present at telomeres, where the cells aging aspect is monitored, throughout the typical cell cycle process.[3] The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1) is a protein that binds at telomere ends.
This gene encodes a telomere specific protein which is a component of the shelterin nucleoprotein complex. This protein is present at telomeres throughout the cell cycle and functions as an inhibitor of telomerase, acting in cis to limit the elongation of individual chromosome ends. The protein has the ultimate use of functioning as an inhibitor of telomerase, a protein enzyme that assists in the elongation of chromosomes by the addition of sequences of TTAGGG to the end of the chromosomes. The protein acts as cis-regulatory elements in the process of limiting the ends of individual chromosomes from elongating as facilitated by telomerase and the TTAGGG sequences. The structure of the protein consists of a dimerization domain close to its Amino terminus, a Carboxyl terminal tail, which is the free carboxyl group that terminates the end of a protein chain and an acidic Amino terminus, which is the free amine group that terminates the start of a protein.
# Biological processes
The protein is also actively involved in biological processes such as the response to drug and the negative regulation of the maintenance of telomere through the process of semi-conservative replication, similar to that of cis. In addition, according to Kaplan and Christopher, the protein is also involved in the biological processes of positive regulation of the polymerization of the microtubule and negative control of the process of DNA replication.[4] This protein is also useful in the biological process of mitosis and the positive regulation of mitosis. It positively regulates the mitotic cell cycle. The protein encoded by the TERF 1 gene is also involved in the biological process of cell division and the negative regulation of the maintenance of telomere facilitated by the enzyme telomerase.
Other than functioning as an inhibitor of the enzyme telomerase in the process of elongation of the ends of chromosomes, the protein has other functions. These functions include the binding of the protein, facilitation in the activity of protein homodimerization, the binding of DNA and facilitation in the activity of protein heterodimerization as well as the binding of the microtubule. Additionally, the protein has a molecular function of binding telomeric DNA and the double-stranded telomeric DNA. The telomeric repeat-binding factor 1 protein is also used in the binding of chromatin and the whole activity of bending of the DNA.[3]
# TERF 1 protein levels correlates with telomere length in colorectal cancer
Telomeres protect the chromosome from degradation by nucleases and end-to-end fusion. The progressive loss of the telomeric ends of chromosomes is an important mechanism in the timing of human cellular aging. Telomeric Repeat Factor 1 (TRF1) is a protein that binds at telomere ends.
To measure the concentrations of TRF1 and the relationships among telomere length, telomerase activity, and TRF1 levels in tumor and normal colorectal mucosa, from normal and tumoral samples of patients who underwent surgery for colorectal cancer we analyzed TRF1 protein concentration, and telomerase activity were analysed.
As result high levels of TRF1 were observed in 68.7% of tumor samples, while the majority of normal samples showed negative or weak TRF1 concentrations. Among the tumor samples, telomere length was significantly associated with TRF1 protein levels.
In conclusion a relationship exists between telomere length and TRF1 abundance protein in tumor samples, which means that TRF1 is an important factor in the tumor progression and maybe a diagnostic factor.
# Interactions
The TERF1 encoded protein has been shown to have interactions with the following; SALL1 (Sal-like1- Drosophila, a protein.), ABL (Abelson murine leukemia viral oncogene homolog, a protein), MAPRE2 (Microtubule-associated protein RP/EB, a protein), ATM (Ataxia telangiectasia mutated, a protein kinase), PINX1 (TERF1-interacting telomerase inhibitor 1), TINF2 (TERF1-interacting telomerase nuclear factor), TNKS2 (Tankyrase, an enzyme) and NME1 (nucleoside diphosphate kinase).In conclusion, as mentioned above, the telomeric repeat-binding factor 1 protein has most of its functions related to the binding of components and regulation of processes.[4]
TERF1 has been shown to interact with:
- Abl gene,[5]
- Ataxia telangiectasia mutated,[5]
- MAPRE1,[6]
- NME1,[7]
- PINX1[8]
- SALL1,[9]
- TINF2,[10][11][12]
- TNKS2,[13][14][15] and
- TNKS.[13][15][16][17][18] | https://www.wikidoc.org/index.php/TERF1 | |
69027874da1fd4296ecaf54243bb7183d933c291 | wikidoc | TERF2 | TERF2
Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.
# Structure & Domains
TERF2 has a similar structure to that of TERF1. Both proteins carry a C-terminus Myb motif and large TERF1-related dimerization domains near their N-terminus. However, both proteins exist exclusively as homodimers and do not heterodimerize with each other, as proven by co-immunoprecipitation assay analysis. Also, TERF2 has a basic N-terminus, differing from TERF1’s acidic N-terminus, and was found to be much more conserved, suggesting that the two proteins have distinct functions.
There are 4 domain categories on the TERF2 protein that allow it to bind to both other proteins in the shelterin protein complex, and to specific types of DNA.
## TERF Homology Domain
The TERF Homology Domain (TRFH) is an area that helps to promote homodimerization of TERF2 with itself. This results in the formation of a quaternary structure that is characteristic of this protein. This TRFH domain also allows TERF2 to bind to and act as a dock for many other types of proteins. The Apollo nuclease, a shelterin accessory factor, uses the TRFH domain as a dock. The recruitment of Apollo by TERF2 allows for telomeric ends formed by DNA synthesis to be processed. By doing so, the telomere ends are able to avoid ATM kinase activation through the creation of a terminal structure. SLX4, which is important in DNA repair by acting as a scaffold for structure-specific DNA repair nucleases, also binds to the TRFH domain of TERF2. The TRFH domain is responsible for other binding events, including RTEL1, and proteins that contain a TBD site.
## Myb Domain
The Myb domain acts by binding to double-stranded telomeric DNA. This region gets its name from a viral protein called Myb derived from the avian myeloblastosis virus. Specifically, the sequence that this Myb domain targets on the DNA is (GGTTAG/CCAATC)n.
## Basic and Hinge Domains
Two other domains also work to bind and influence the activity of proteins associated with the TERF2 protein. The basic domain sits at the N-terminal, and has two main functions: the prevention of t-loop excision by XRCC3, and the inhibition of SLX4. The final domain of TERF2 is called the hinge domain. This domain contains a motif for binding the shelterin protein TIN2, which acts as a stabilizing protein, connecting units that are attached to double stranded and single stranded DNA. This domain also is responsible for binding to RAP1, and helps to inhibit RNF168 recruitment at telomeres.
# Function
This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length, and plays a key role in the protective activity of telomeres. While having similar telomere binding activity and domain organization, TERF2 differs from TERF1 in that its N terminus is basic rather than acidic.
## T-Loop Formation
Telomeric ends are structurally similar to double-stranded breaks on the chromosome. To prevent the cellular DNA repair machinery from mistakenly identifying telomeres as chromosome breaks, t-loops are formed in which the 3’ TTAGGG overhang of the telomere loops back into the DNA duplex. TERF2 promotes t-loop formation by preferentially binding to a telomeric double-stranded DNA duplex containing a 3’ TTAGGG single-stranded overhang. If the 3’ TTAGGG overhang is not present, TERF2 will not bind. Once bound, it migrates to the t-loop junction where the single-stranded overhang invades the double-stranded region upstream. No other shelterin protein has been shown to promote this process and studies have demonstrated that deletion of TERF2 prevents t-loop formation, leading to excessive loss of telomeric DNA and early cell death.
## ATM Kinase Prevention
TERF2 plays a central role in preventing ATM kinase DNA damage response. It binds telomeric dsDNA and prevents telomeres from activating ATM kinase. This interaction of TERF2 with ATM is believed to be relevant to the mechanism by which TERF2 blocks ATM signaling. Because of its oligomeric nature, TERF2 could potentially cross-link ATM monomers and hold the kinase in its inactive dimeric state, thereby blocking amplification of the ATM signal at an early step in its activation. However, because mutations in the TERF2 dimerization domain destabilize the protein, it has not been possible to test the contribution of TERF2 oligomerization on ATM repression directly. Removal of TERF2 induces ATM-dependent apoptosis by localizing the active, phosphorylated form of ATM to unprotected chromosome ends. Since TERF2 specifically binds at telomeres and remains there when DNA damage is induced, it is unlikely to interfere with activation of the ATM kinase at different sites of DNA damage. Therefore, TERF2 could act as a telomere-specific inhibitor of ATM kinase.
## TERF2 Knockout Effects
Conditional deletion of TERF2 in mice cells effectively removes the shelterin nucleoprotein complex. As a result of removing this complex, several unwanted DNA damage response pathways are activated, including ATM kinase signaling, ATR kinase signaling, non-homologous end-joining (NHEJ), alt-NHEJ, C-NHEJ, 5' resection, and homology directed repair (HDR). These repair pathways (in the presence of P53 knockout and Cre) often contribute to the phenotype where chromosome ends are connected to each other in a very long chain, which can be visualized by a combination of a DAPI stain and fluorescence in situ hybridization (FISH) technique.
# Interactions
TERF2 is also known to recruit certain client proteins, also known as accessory factors. These client proteins are often recruited to TERF2 for a specific function at a specific time, often temporarily. The TRFH domain contains a F120 residue, which is the binding site of TERF2 where it recruits client proteins. These client proteins also contain a TRFH binding motif, which consists of a conserved 6-amino acid sequence of the following formula: YxLxP, where "x" can be any amino acid substituted. The above-mentioned Apollo nuclease (one of many TERF2's client proteins) also contains the formulaic motif; its specific motif sequence is YLLTP.
TERF1 also demonstrates similar client protein recruitment mechanism as TERF2, except that it diverges at two concepts: 1) the TRFH of TERF1 contains a F142 residue, 2) the client proteins specific for TERF1 contain the TRFH binding motif sequence of FxLxP, where the amino acid Y (tyrosine) is replaced with F (phenylalanine).
TERF2 has also been shown to interact with:
- Ku70,
- MRE11A,
- Nibrin and
- Rad50,
- TERF2IP, and
- Werner syndrome ATP-dependent helicase.
# Disease Relevance of TERF2
## Cancer
Telomerase is an enzyme that works to create telomeric ends for DNA, and it is thought to play important roles in the development of cancer. Specifically, telomeric stability is known to be a common occurrence in cancer cells. Along with the telomerase, the shelterin complex, and TERF2 and TERF1 specifically, also have been noted to control the lengths of telomeres formed by these telomerases. Shelterin works to protect telomeres against unsuitable activation of the DNA damage response pathway, as noted in the function section above. TERF2 as part of the shelterin complex, has been known to block the ATM signaling pathways and prevent chromosome end fusion. In cancer cells, TERF2 phosphorylation by extracellular signal-regulated kinase (ERK1/2) is a controlling factor in the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) that affect telomeric stability. Additionally, when TERF2 was non-phosphorylated in melanoma cells, there was a cell induced DNA damage response, arresting growth and causing tumor reversion. Studies have found that in tumor cells, TERF2 levels are observed to be high, and this raised level of TERF2 contributes to oncogenesis in a variety of ways. This high level of TERF2 decreases the ability to recruit and activate natural killer cells in human tumor cells. One study used a dominant negative form of TERF2ΔBΔC, to inhibit TERF2, and found that it could induce a reversion malignant phenotype in human melanoma cells. Therefore, over-expression of TERF2ΔBΔC, and therefore blocking of TERF2, induced apoptosis and reduced tumourigenicity in certain cell lines. Additionally, upregulation of TERF2 may be the cause of the establishment and maintenance of short telomeres. These short telomeres increase chromosomal instability, and increase the chances of certain cancers progressing in the body, such as with leukemia. In gastric mucosa tissues, the expression of TERF2 proteins was significantly higher than normal, and this over-expression of TERF2, along with over-expression of TERF1, TIN2, TERT, and BRCA1 protein transposition, may cause a reduction in telomere length, further contributing to multistage carcinogenesis of gastric cancer. | TERF2
Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene.[1] It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange,[2] where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.
# Structure & Domains
TERF2 has a similar structure to that of TERF1. Both proteins carry a C-terminus Myb motif and large TERF1-related dimerization domains near their N-terminus.[2] However, both proteins exist exclusively as homodimers and do not heterodimerize with each other, as proven by co-immunoprecipitation assay analysis.[2] Also, TERF2 has a basic N-terminus, differing from TERF1’s acidic N-terminus, and was found to be much more conserved, suggesting that the two proteins have distinct functions.[3]
There are 4 domain categories on the TERF2 protein that allow it to bind to both other proteins in the shelterin protein complex, and to specific types of DNA.
## TERF Homology Domain
The TERF Homology Domain (TRFH) is an area that helps to promote homodimerization of TERF2 with itself. This results in the formation of a quaternary structure that is characteristic of this protein. This TRFH domain also allows TERF2 to bind to and act as a dock for many other types of proteins. The Apollo nuclease, a shelterin accessory factor, uses the TRFH domain as a dock. The recruitment of Apollo by TERF2 allows for telomeric ends formed by DNA synthesis to be processed. By doing so, the telomere ends are able to avoid ATM kinase activation through the creation of a terminal structure.[4] SLX4, which is important in DNA repair by acting as a scaffold for structure-specific DNA repair nucleases, also binds to the TRFH domain of TERF2.[5] The TRFH domain is responsible for other binding events, including RTEL1, and proteins that contain a TBD site.
## Myb Domain
The Myb domain acts by binding to double-stranded telomeric DNA. This region gets its name from a viral protein called Myb derived from the avian myeloblastosis virus. Specifically, the sequence that this Myb domain targets on the DNA is (GGTTAG/CCAATC)n.
## Basic and Hinge Domains
Two other domains also work to bind and influence the activity of proteins associated with the TERF2 protein. The basic domain sits at the N-terminal, and has two main functions: the prevention of t-loop excision by XRCC3, and the inhibition of SLX4. The final domain of TERF2 is called the hinge domain. This domain contains a motif for binding the shelterin protein TIN2, which acts as a stabilizing protein, connecting units that are attached to double stranded and single stranded DNA.[6] This domain also is responsible for binding to RAP1, and helps to inhibit RNF168 recruitment at telomeres.
# Function
This protein is present at telomeres in metaphase of the cell cycle, is a second negative regulator of telomere length, and plays a key role in the protective activity of telomeres. While having similar telomere binding activity and domain organization, TERF2 differs from TERF1 in that its N terminus is basic rather than acidic.[3]
## T-Loop Formation
Telomeric ends are structurally similar to double-stranded breaks on the chromosome. To prevent the cellular DNA repair machinery from mistakenly identifying telomeres as chromosome breaks, t-loops are formed in which the 3’ TTAGGG overhang of the telomere loops back into the DNA duplex. TERF2 promotes t-loop formation by preferentially binding to a telomeric double-stranded DNA duplex containing a 3’ TTAGGG single-stranded overhang. If the 3’ TTAGGG overhang is not present, TERF2 will not bind. Once bound, it migrates to the t-loop junction where the single-stranded overhang invades the double-stranded region upstream. No other shelterin protein has been shown to promote this process and studies have demonstrated that deletion of TERF2 prevents t-loop formation, leading to excessive loss of telomeric DNA and early cell death.[8]
## ATM Kinase Prevention
TERF2 plays a central role in preventing ATM kinase DNA damage response. It binds telomeric dsDNA and prevents telomeres from activating ATM kinase. This interaction of TERF2 with ATM is believed to be relevant to the mechanism by which TERF2 blocks ATM signaling. Because of its oligomeric nature, TERF2 could potentially cross-link ATM monomers and hold the kinase in its inactive dimeric state, thereby blocking amplification of the ATM signal at an early step in its activation. However, because mutations in the TERF2 dimerization domain destabilize the protein, it has not been possible to test the contribution of TERF2 oligomerization on ATM repression directly. Removal of TERF2 induces ATM-dependent apoptosis by localizing the active, phosphorylated form of ATM to unprotected chromosome ends. Since TERF2 specifically binds at telomeres and remains there when DNA damage is induced, it is unlikely to interfere with activation of the ATM kinase at different sites of DNA damage. Therefore, TERF2 could act as a telomere-specific inhibitor of ATM kinase.[9]
## TERF2 Knockout Effects
Conditional deletion of TERF2 in mice cells effectively removes the shelterin nucleoprotein complex. As a result of removing this complex, several unwanted DNA damage response pathways are activated, including ATM kinase signaling, ATR kinase signaling, non-homologous end-joining (NHEJ), alt-NHEJ, C-NHEJ, 5' resection, and homology directed repair (HDR).[10] These repair pathways (in the presence of P53 knockout and Cre) often contribute to the phenotype where chromosome ends are connected to each other in a very long chain, which can be visualized by a combination of a DAPI stain and fluorescence in situ hybridization (FISH) technique.
# Interactions
TERF2 is also known to recruit certain client proteins, also known as accessory factors. These client proteins are often recruited to TERF2 for a specific function at a specific time, often temporarily. The TRFH domain contains a F120 residue, which is the binding site of TERF2 where it recruits client proteins. These client proteins also contain a TRFH binding motif, which consists of a conserved 6-amino acid sequence of the following formula: YxLxP, where "x" can be any amino acid substituted.[11] The above-mentioned Apollo nuclease (one of many TERF2's client proteins) also contains the formulaic motif; its specific motif sequence is YLLTP.
TERF1 also demonstrates similar client protein recruitment mechanism as TERF2, except that it diverges at two concepts: 1) the TRFH of TERF1 contains a F142 residue, 2) the client proteins specific for TERF1 contain the TRFH binding motif sequence of FxLxP, where the amino acid Y (tyrosine) is replaced with F (phenylalanine).
TERF2 has also been shown to interact with:
- Ku70,[12]
- MRE11A,[13]
- Nibrin[13] and
- Rad50,[13][14]
- TERF2IP,[13][14][15] and
- Werner syndrome ATP-dependent helicase.[16]
# Disease Relevance of TERF2
## Cancer
Telomerase is an enzyme that works to create telomeric ends for DNA, and it is thought to play important roles in the development of cancer. Specifically, telomeric stability is known to be a common occurrence in cancer cells.[17] Along with the telomerase, the shelterin complex, and TERF2 and TERF1 specifically, also have been noted to control the lengths of telomeres formed by these telomerases. Shelterin works to protect telomeres against unsuitable activation of the DNA damage response pathway, as noted in the function section above. TERF2 as part of the shelterin complex, has been known to block the ATM signaling pathways and prevent chromosome end fusion. In cancer cells, TERF2 phosphorylation by extracellular signal-regulated kinase (ERK1/2) is a controlling factor in the major pro-oncogenic signaling pathways (RAS/RAF/MEK/ERK) that affect telomeric stability.[17] Additionally, when TERF2 was non-phosphorylated in melanoma cells, there was a cell induced DNA damage response, arresting growth and causing tumor reversion.[17] Studies have found that in tumor cells, TERF2 levels are observed to be high, and this raised level of TERF2 contributes to oncogenesis in a variety of ways.[18][19][20] This high level of TERF2 decreases the ability to recruit and activate natural killer cells in human tumor cells.[18] One study used a dominant negative form of TERF2ΔBΔC, to inhibit TERF2, and found that it could induce a reversion malignant phenotype in human melanoma cells.[19] Therefore, over-expression of TERF2ΔBΔC, and therefore blocking of TERF2, induced apoptosis and reduced tumourigenicity in certain cell lines.[19] Additionally, upregulation of TERF2 may be the cause of the establishment and maintenance of short telomeres.[20] These short telomeres increase chromosomal instability, and increase the chances of certain cancers progressing in the body, such as with leukemia.[20] In gastric mucosa tissues, the expression of TERF2 proteins was significantly higher than normal, and this over-expression of TERF2, along with over-expression of TERF1, TIN2, TERT, and BRCA1 protein transposition, may cause a reduction in telomere length, further contributing to multistage carcinogenesis of gastric cancer.[21] | https://www.wikidoc.org/index.php/TERF2 | |
0531c804e9d5c2423d4be3f1223b5c988d273b28 | wikidoc | TFB1M | TFB1M
Dimethyladenosine transferase 1, mitochondrial; Transcription factor B1, mitochondrial is a mitochondrial enzyme that in 12-Eiael mag ingay is encoded by the TFB1M gene.
TFB1M is a mitochondrial methyltransferase, which uses S-adenosyl methionine to dimethylate two highly conserved adenosine residues at the 3'-end of the mitochondrial 12S rRNA thereby regulating the assembly or stability of the small subunit of the mitochondrial ribosome.
Additionally, TFB1M has been demonstrated to stimulate transcription from promoter templates in an in vitro system containing recombinant mitochondrial RNA polymerase and TFAM. There are no experimental data demonstrating that this function occurs in vivo.
# Interactions
TFB1M has been shown to interact with TFAM. | TFB1M
Dimethyladenosine transferase 1, mitochondrial; Transcription factor B1, mitochondrial is a mitochondrial enzyme that in 12-Eiael mag ingay is encoded by the TFB1M gene.[1][2][3]
TFB1M is a mitochondrial methyltransferase, which uses S-adenosyl methionine to dimethylate two highly conserved adenosine residues at the 3'-end of the mitochondrial 12S rRNA thereby regulating the assembly or stability of the small subunit of the mitochondrial ribosome.[2][4][5]
Additionally, TFB1M has been demonstrated to stimulate transcription from promoter templates in an in vitro system containing recombinant mitochondrial RNA polymerase and TFAM.[6] There are no experimental data demonstrating that this function occurs in vivo.
# Interactions
TFB1M has been shown to interact with TFAM.[7] | https://www.wikidoc.org/index.php/TFB1M | |
9c9b2a2c6f6942f733924cca99928c7ed0d79909 | wikidoc | TFCP2 | TFCP2
Alpha-globin transcription factor CP2 is a protein that in humans is encoded by the TFCP2 gene.
TFCP2 is also called Late SV40 factor (LSF) and it is induced by well known oncogene AEG-1. Late SV40 factor (LSF) also acts as an oncogene in hepatocellular carcinoma. Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).
Along with its main oncogene function in hepatocellular carcinoma (HCC) it plays multifaceted role in chemoresistance, epithelial-mesenchymal transition (EMT), allergic response, inflammation and Alzheimer's disease. The small molecule FQI1 (factor quinolinone inhibitor 1) prevents LSF from binding to HCC DNA which results in HCC cell death.
# Interactions
TFCP2 has been shown to interact with APBB1 and RNF2. | TFCP2
Alpha-globin transcription factor CP2 is a protein that in humans is encoded by the TFCP2 gene.[1][2]
TFCP2 is also called Late SV40 factor (LSF) and it is induced by well known oncogene AEG-1.[3] Late SV40 factor (LSF) also acts as an oncogene in hepatocellular carcinoma.[4] Late SV40 factor (LSF) enhances angiogenesis by transcriptionally up-regulating matrix metalloproteinase-9 (MMP9).[5]
Along with its main oncogene function in hepatocellular carcinoma (HCC) it plays multifaceted role in chemoresistance, epithelial-mesenchymal transition (EMT), allergic response, inflammation and Alzheimer's disease.[4][6] The small molecule FQI1 (factor quinolinone inhibitor 1) prevents LSF from binding to HCC DNA which results in HCC cell death.[4][6][7]
# Interactions
TFCP2 has been shown to interact with APBB1[8] and RNF2.[9] | https://www.wikidoc.org/index.php/TFCP2 | |
54cbcf05eb29bf5b1362d4796d7e5f23e316a88e | wikidoc | TFIIA | TFIIA
Transcription Factor TFIIA
Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA polymerase II. Other GTFs include TFIID, a complex composed of the TATA binding protein TBP and TBP-associated factors (TAFs), as well as the factors TFIIB, TFIIE, TFIIF, and TFIIH. Together, these factors are responsible for promoter recognition and the formation of a transcription preinitiation complex (PIC) capable of initiating RNA synthesis from a DNA template.
Functions of TFIIA
TFIIA interacts with the TBP subunit of TFIID and aids in the binding of TBP to TATA-box containing promoter DNA. Although TFIIA does not recognize DNA itself, its interactions with TBP allow it to stabilize and facilitate formation of the PIC. Binding of TFIIA to TBP also results in the exclusion of negative (repressive) factors that might otherwise bind to TBP and interfere with PIC formation. TFIIA also acts as a coactivator for some transcriptional activators, assisting with their ability to increase, or activate, transcription. The requirement for TFIIA in in vitro (cell-free) transcription systems has been variable, and it can be considered either as a GTF and/or a loosely associated TAF-like coactivator. Genetic analysis in yeast has shown that TFIIA is essential for viability.
TFIIA Genes
TFIIA is encoded by two separate genes, one of which encodes a large subunit (TFIIAalpha/beta, TFIIAL, TOA1; gene name GTF2A1) and another which encodes a small subunit (TFIIAgamma, TFIIAS, TOA2; gene name GTF2A2). In humans, the sizes of the encoded proteins are approximately 55 kD and 12 kD. Both genes are present in species ranging from humans to yeast, and their protein products interact to form a complex composed of a beta barrel domain and an alpha helical bundle domain. It is the N-terminal and C-terminal regions of the large subunit that participate in interactions with the small subunit. These regions are separated by another domain whose sequence is always present in large subunits from various species but whose size varies and whose sequence is poorly conserved. The large subunit is often observed to be proteolytically processed into two smaller subunits (alpha and beta) of approximately 35 kD and 19 kD. A second gene encoding a large TFIIA subunit has been found in some higher eukaryotes. This gene, ALF/TFIIAtau (gene name GTF2A1LF) is expressed only in oocytes and spermatocytes, suggesting it has a TFIIA-like regulatory role for gene expression only in germ cells. | TFIIA
Transcription Factor TFIIA
Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA polymerase II. Other GTFs include TFIID, a complex composed of the TATA binding protein TBP and TBP-associated factors (TAFs), as well as the factors TFIIB, TFIIE, TFIIF, and TFIIH. Together, these factors are responsible for promoter recognition and the formation of a transcription preinitiation complex (PIC) capable of initiating RNA synthesis from a DNA template.
Functions of TFIIA
TFIIA interacts with the TBP subunit of TFIID and aids in the binding of TBP to TATA-box containing promoter DNA. Although TFIIA does not recognize DNA itself, its interactions with TBP allow it to stabilize and facilitate formation of the PIC. Binding of TFIIA to TBP also results in the exclusion of negative (repressive) factors that might otherwise bind to TBP and interfere with PIC formation. TFIIA also acts as a coactivator for some transcriptional activators, assisting with their ability to increase, or activate, transcription. The requirement for TFIIA in in vitro (cell-free) transcription systems has been variable, and it can be considered either as a GTF and/or a loosely associated TAF-like coactivator. Genetic analysis in yeast has shown that TFIIA is essential for viability.
TFIIA Genes
TFIIA is encoded by two separate genes, one of which encodes a large subunit (TFIIAalpha/beta, TFIIAL, TOA1; gene name GTF2A1)[1] and another which encodes a small subunit (TFIIAgamma, TFIIAS, TOA2; gene name GTF2A2).[2] In humans, the sizes of the encoded proteins are approximately 55 kD and 12 kD. Both genes are present in species ranging from humans to yeast, and their protein products interact to form a complex composed of a beta barrel domain and an alpha helical bundle domain. It is the N-terminal and C-terminal regions of the large subunit that participate in interactions with the small subunit. These regions are separated by another domain whose sequence is always present in large subunits from various species but whose size varies and whose sequence is poorly conserved. The large subunit is often observed to be proteolytically processed into two smaller subunits (alpha and beta) of approximately 35 kD and 19 kD. A second gene encoding a large TFIIA subunit has been found in some higher eukaryotes. This gene, ALF/TFIIAtau (gene name GTF2A1LF) is expressed only in oocytes and spermatocytes, suggesting it has a TFIIA-like regulatory role for gene expression only in germ cells. | https://www.wikidoc.org/index.php/TFIIA | |
dcd4fe02098379610c675747141ef64f769a14ad | wikidoc | THAP1 | THAP1
THAP domain-containing protein 1 is a protein that in humans is encoded by the THAP1 gene. The synonyme is DYT6 (Dystonia 6).
# Function
The protein encoded by this gene contains a THAP domain, a conserved DNA-binding domain. This protein colocalizes with the apoptosis response protein PAWR/PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. Alternatively spliced transcript variants encoding distinct isoforms have been observed.
# Interactions
THAP1 has been shown to interact with PAWR.
# Clinical significance
Thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) is a DNA-binding protein that has been associated with DYT6 dystonia, a hereditary movement disorder involving sustained, involuntary muscle contractions. | THAP1
THAP domain-containing protein 1 is a protein that in humans is encoded by the THAP1 gene. The synonyme is DYT6 (Dystonia 6).[1][2][3]
# Function
The protein encoded by this gene contains a THAP domain, a conserved DNA-binding domain. This protein colocalizes with the apoptosis response protein PAWR/PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[3]
# Interactions
THAP1 has been shown to interact with PAWR.[2]
# Clinical significance
Thanatos-associated [THAP] domain-containing apoptosis-associated protein 1 (THAP1) is a DNA-binding protein that has been associated with DYT6 dystonia, a hereditary movement disorder involving sustained, involuntary muscle contractions.[4][5] | https://www.wikidoc.org/index.php/THAP1 | |
1f2a6ae21e410cd69d542b55b4b6b09555a5059a | wikidoc | TIMP1 | TIMP1
TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein is a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
# Function
TIMP1 is an inhibitory molecule that regulates matrix metalloproteinases (MMPs), and disintegrin-metalloproteinases (ADAMs and ADAMTSs). In regulating MMPs, TIMP1 plays a crucial role in extracellular matrix (ECM) composition, wound healing, and pregnancy.
The dysregulated activity of TIMP1 has been implicated in cancer. In pregnancy, TIMP1 plays a regulatory role in the process of implantation, particularly the cytotrophoblast invasion of the uterine endometrium. Additionally, it plays a role in regulating the transcriptional profile of fetal and placental tissues associated with the early stages of pregnancy. Studies attribute this role to a mechanism involving the chromatin structure at the TIMP1 promoter region, implicating new pharmaceutical possibilities for the therapeutic regulation of TIMP1. Accordingly, TIMP1 can be manipulated in vitro using techniques, like the TIMP1 knock-out.
# Other names
- Erythroid potentiating activity (EPA)
- Human collagenase inhibitor (HCI)
# Regulation of TIMP expression
Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.
In adrenocortical cells the trophic hormone ACTH induces expression of TIMP-1 and the increase in TIMP expression is also associated with decreased collagenase activity.
Increased expression of TIMP1 has been found to be associated with worse prognosis of various tumors, such as laryngeal carcinoma or melanoma. | TIMP1
TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein that is expressed from the several tissues of organisms.
This protein is a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.
# Function
TIMP1 is an inhibitory molecule that regulates matrix metalloproteinases (MMPs), and disintegrin-metalloproteinases (ADAMs and ADAMTSs).[1] In regulating MMPs, TIMP1 plays a crucial role in extracellular matrix (ECM) composition, wound healing,[2] and pregnancy.[3][4][5]
The dysregulated activity of TIMP1 has been implicated in cancer.[6] In pregnancy, TIMP1 plays a regulatory role in the process of implantation, particularly the cytotrophoblast invasion of the uterine endometrium.[7] Additionally, it plays a role in regulating the transcriptional profile of fetal and placental tissues associated with the early stages of pregnancy.[8] Studies attribute this role to a mechanism involving the chromatin structure at the TIMP1 promoter region, implicating new pharmaceutical possibilities for the therapeutic regulation of TIMP1. Accordingly, TIMP1 can be manipulated in vitro using techniques, like the TIMP1 knock-out.[9][10][11]
# Other names
- Erythroid potentiating activity (EPA)
- Human collagenase inhibitor (HCI)
# Regulation of TIMP expression
Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.[12]
In adrenocortical cells the trophic hormone ACTH induces expression of TIMP-1 and the increase in TIMP expression is also associated with decreased collagenase activity.[13]
Increased expression of TIMP1 has been found to be associated with worse prognosis of various tumors, such as laryngeal carcinoma [14] or melanoma.[15] | https://www.wikidoc.org/index.php/TIMP1 | |
4dda54f000402c7daf39cfa8464b3dfe159319ce | wikidoc | TIMP2 | TIMP2
Tissue inhibitor of metalloproteinases 2 (TIMP2) is a gene and a corresponding protein. The gene is a member of the TIMP gene family. The protein is thought to be a metastasis suppressor.
# Function
The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMP), a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. TIMP2 functions as both an MMP inhibitor and an activator. TIMPs inhibit active MMPs, but different TIMPs inhibit different MMPs better than others. For example, TIMP-1 inhibits MMP-7, MMP-9, MMP-1 and MMP-3 better than TIMP-2, and TIMP-2 inhibits MMP-2 more effectively than other TIMPs.
In melanocytic cells TIMP2 gene expression may be regulated by MITF.
A more recent discovery is that TIMP2 plays an important role in hippocampal function and cognitive function. It plays a critical role in the benefit conferred to old mice when given human umbilical cord blood.
# Interactions
TIMP2 has been shown to interact with:
- MMP14 and
- MMP2. | TIMP2
Tissue inhibitor of metalloproteinases 2 (TIMP2) is a gene and a corresponding protein. The gene is a member of the TIMP gene family. The protein is thought to be a metastasis suppressor.[citation needed]
# Function
The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMP), a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix.[1] TIMP2 functions as both an MMP inhibitor and an activator. TIMPs inhibit active MMPs, but different TIMPs inhibit different MMPs better than others. For example, TIMP-1 inhibits MMP-7, MMP-9, MMP-1 and MMP-3 better than TIMP-2, and TIMP-2 inhibits MMP-2 more effectively than other TIMPs.[2]
In melanocytic cells TIMP2 gene expression may be regulated by MITF.[3]
A more recent discovery is that TIMP2 plays an important role in hippocampal function and cognitive function. It plays a critical role in the benefit conferred to old mice when given human umbilical cord blood.[4][5]
# Interactions
TIMP2 has been shown to interact with:
- MMP14[6] and
- MMP2.[7][8][9][10] | https://www.wikidoc.org/index.php/TIMP2 | |
9111e1412640c30443ce5dbd4a163ac7f70d80ff | wikidoc | TIP39 | TIP39
Tuberoinfundibular peptide of 39 residues is a protein that in humans is encoded by the PTH2 gene.
TIP39 is related to parathyroid hormone (PTH; MIM 168450) and PTH-related protein (PTHRP; MIM 168470) and is a ligand for PTH receptor-2 (PTHR2; MIM 601469) (John et al., 2002).
The molecular interaction of TIP39 with the PTH2 receptor has been characterized in full 3D molecular detail, identifying among other residues, Tyr-318 in transmembrane helix 5 as a key residue for high affinity binding | TIP39
Tuberoinfundibular peptide of 39 residues is a protein that in humans is encoded by the PTH2 gene.[1][2]
TIP39 is related to parathyroid hormone (PTH; MIM 168450) and PTH-related protein (PTHRP; MIM 168470) and is a ligand for PTH receptor-2 (PTHR2; MIM 601469) (John et al., 2002).[supplied by OMIM][2]
The molecular interaction of TIP39 with the PTH2 receptor has been characterized in full 3D molecular detail, identifying among other residues, Tyr-318 in transmembrane helix 5 as a key residue for high affinity binding [3] | https://www.wikidoc.org/index.php/TIP39 | |
7fd63d995d13e2f1343af1e3dc08bff65ccf5d30 | wikidoc | TLR10 | TLR10
Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene. TLR10 has also been designated as CD290 (cluster of differentiation 290).
TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells. This makes TLR10 unique among the TLR family. No ligand is currently known for TLR10.
# Function
The protein encoded by this gene is a member of the toll-like receptor (TLR) family which play a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.
TLR10 is unique among the TLR family in having an anti-inflammatory function, rather than a pro-inflammatory function similar to the other TLR family members. This was discovered by over-expressing TLR10 in human cell lines and using antibody-mediated engagement of the receptor on primary human cells. When TLR10 is activated in this manner, it suppresses the amount of cytokines produced, as compared to control cells. TLR10 engagement also has long-term effects on monocyte and B cell activation/differentiation by suppressing the transcription of activation markers. TLR10's mechanism of action is not yet known but activation of the receptor has been shown to suppress NF-κB, MAP kinase and Akt signaling events stimulated by TLR and CD40 ligands. Currently, no ligand has been identified for this receptor.
# Expression
TLR10 has been transcriptionally shown to be expressed in secondary lymphoid tissues such as the spleen, lymph nodes, and tonsils. More specifically, protein level expression of TLR10 has been shown on the surface of B cells, monocytes and neutrophils; but not on T cells. Monocytes have the highest expression of TLR10 among these cell types but the overall expression of TLR10 is low compared to other TLRs. TLR10 has also been shown to be produced intracellularly in neutrophils and B cells differentiating into plasma cells.
Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. | TLR10
Toll-like receptor 10 is a protein that in humans is encoded by the TLR10 gene.[1] TLR10 has also been designated as CD290 (cluster of differentiation 290).
TLR10 has not been extensively studied because it is a pseudogene in mice, though all other mammalian species contain an intact copy of the TLR10 gene. Unlike other TLRs, TLR10 does not activate the immune system and has instead been shown to suppress inflammatory signaling on primary human cells.[2] This makes TLR10 unique among the TLR family. No ligand is currently known for TLR10.
# Function
The protein encoded by this gene is a member of the toll-like receptor (TLR) family which play a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity.
TLR10 is unique among the TLR family in having an anti-inflammatory function, rather than a pro-inflammatory function similar to the other TLR family members. This was discovered by over-expressing TLR10 in human cell lines and using antibody-mediated engagement of the receptor on primary human cells. When TLR10 is activated in this manner, it suppresses the amount of cytokines produced, as compared to control cells. TLR10 engagement also has long-term effects on monocyte and B cell activation/differentiation by suppressing the transcription of activation markers. TLR10's mechanism of action is not yet known but activation of the receptor has been shown to suppress NF-κB, MAP kinase and Akt signaling events stimulated by TLR and CD40 ligands.[3] Currently, no ligand has been identified for this receptor.
# Expression
TLR10 has been transcriptionally shown to be expressed in secondary lymphoid tissues such as the spleen, lymph nodes, and tonsils. More specifically, protein level expression of TLR10 has been shown on the surface of B cells, monocytes and neutrophils; but not on T cells. Monocytes have the highest expression of TLR10 among these cell types but the overall expression of TLR10 is low compared to other TLRs. TLR10 has also been shown to be produced intracellularly in neutrophils and B cells differentiating into plasma cells.
Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene.[4] | https://www.wikidoc.org/index.php/TLR10 | |
4a08c59693b75a8edcc8790adf661fa99ec05030 | wikidoc | TLR 1 | TLR 1
TLR 1 is a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system. TLR1 recognizes pathogen-associated molecular pattern with a specificity for gram-positive bacteria. TLR1 has also been designated as CD281 (cluster of differentiation 281).
TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene.
TLR1 recognises peptidoglycan and (triacyl) lipoproteins in concert with TLR2 (as a heterodimer). Toll-like receptors, including TLR-1, found on the epithelial cell layer that lines the small and large intestine are important players in the management of the gut microbiota and detection of pathogens. It is also found on the surface of macrophages and neutrophils.
# Interactions
TLR 1 has been shown to interact with TLR 2. | TLR 1
TLR 1 is a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system.[1][2] TLR1 recognizes pathogen-associated molecular pattern with a specificity for gram-positive bacteria. TLR1 has also been designated as CD281 (cluster of differentiation 281).
TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene.[3]
TLR1 recognises peptidoglycan and (triacyl) lipoproteins in concert with TLR2 (as a heterodimer).[4][5] Toll-like receptors, including TLR-1, found on the epithelial cell layer that lines the small and large intestine are important players in the management of the gut microbiota and detection of pathogens.[6] It is also found on the surface of macrophages and neutrophils.
# Interactions
TLR 1 has been shown to interact with TLR 2.[7] | https://www.wikidoc.org/index.php/TLR_1 | |
f185f35f90b933bf6756046d41172ffb51c426ca | wikidoc | TLR 3 | TLR 3
TLR 3 is a member of the Toll-like receptor family of pattern recognition receptors of the innate immune system. Discovered in 2001, TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as influenza. Upon recognition, TLR 3 induces the activation of NF-kB to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5.
# Structure
The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute. TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, making it a glycoprotein, but on one face (including the interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively-charged amino acids, which may be a binding site for negatively-charged double-stranded RNA.
Despite being a glycoprotein, TLR3 crystallises readily - a prerequisite for structural analysis by x-ray crystallography. | TLR 3
TLR 3 is a member of the Toll-like receptor family of pattern recognition receptors of the innate immune system. Discovered in 2001,[1] TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as influenza. Upon recognition, TLR 3 induces the activation of NF-kB to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5.
# Structure
The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute.[2] TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered with sugar molecules, making it a glycoprotein, but on one face (including the interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively-charged amino acids, which may be a binding site for negatively-charged double-stranded RNA.
Despite being a glycoprotein, TLR3 crystallises readily - a prerequisite for structural analysis by x-ray crystallography. | https://www.wikidoc.org/index.php/TLR_3 | |
537a2cd4b9ad8b4c056684295d2701c533931702 | wikidoc | TMCO4 | TMCO4
Transmembrane and coiled-coil domains 4, TMCO4, is a protein in humans that is encoded by the TMCO4 gene. Currently, its function is not well defined. It is transmembrane protein that is predicted to cross the endoplasmic reticulum membrane three times. TMCO4 interacts with other proteins known to play a role in cancer development, hinting at a possible role in the disease of cancer.
# Gene
TMCO4 is located on the minus strand of the first chromosome at 1p36.13. The gene consists of 118,172 base pairs stretching from base pair 19,682,213 through 19,800,385. There are no common aliases for TMCO4. Genes CAPZB and LOC105376823 neighbor TMCO4 on chromosome 1. TMCO4 consists of 16 exons.
# mRNA
There are twenty mRNA transcript variants (X1-X20) produced through different combinations of sixteen different exons. The most common variant is X1, which includes all exons and spans the entire 118,172 base pairs.
# Protein
## Primary sequence
The most common protein encoded by TMCO4 is 634 amino acids in length with accession number XP_011539488.1.
## General properties and composition
The molecular weight of TMCO4 is 67.9 kiloDaltons. The isoelectric point is 5.48. As a whole protein, TMCO4 does not have abnormal amino acid distributions. It does have three long stretches of no charge that correspond with the location of the three different transmembrane regions. The first cytosolic domain of TMCO4 does have abnormally high amounts of leucine and glutamic acid and abnormally low amounts of asparagine. The larger lumenal domain of TMCO4 also has an abnormally low amount of asparagine and phenylalanine.
## Protein features
Two main areas of interest within the TMCO4 protein are the three transmembrane regions and the large Abhydrolase region. The N-terminus of TMCO4 is predicted to be within the cytosol of the cell, and the C-terminus is predicted to be within the lumen of the endoplasmic retiticulum. TMCO4 is also predicted to have a leucine zipper and a large coiled coil domain.
## Secondary structure
The secondary structure of TMCO4 is predicted to be dominated by alpha helices based on predictions by iTASSER software.
## Post-translational modifications
Many phosphorylation sites were predicted for the two cytosolic regions of TMCO4. O-linked glycosylation sites were predicted to occur in the end of the second lumenal region of TMCO4. These predicted sites can be seen on both the schematic illustration of TMCO4 found above, or in the conceptual translation of TMCO4 found below.
## Subcellular localization
TMCO4 is consistently predicted to be located in the endoplasmic reticulum membrane across many homologs.
## Interacting proteins
TMCO4 has been found to interact with many proteins. One protein of interest that TMCO4 interacts with is FLT1. FLT1 is a VEGF receptor. VEGF is known to play a significant role in cancer development. Other proteins that TMCO4 has been experimentally shown to interact with are UBB, UBC, KPTN, and BVLF1. UBB and UBC are polyubiquitins that target molecules for degradation, suggesting that TMCO4 is degraded at some point. KPTN is a protein that is essential in neuromorphogenesis. BVLF1 is an Epstein-Barr virus protein.
# Homology
## Paralogs
TMCO4 does not have any paralogs.
## Orthologs
Orthologs to TMCO4 can be found in bacteria, protists, plants, fungi, trichoplax, ivertebrates, fish, amphibians, reptiles, birds and mammals. Some of these orthologs can be found in the table below. The orthologs are sorted in descending order of date of evolution from humans and then descending order of percent sequence identity. TMCO4 is a fast evolving gene that has been highly conserved throughout evolution. Regions of TMCO4 that are highly conserved across the orthologs include the various transmembrane domains and the abhydrolase region.
# Expression
TMCO4 is highly expressed in many tissues. Highest expression occurs within the prostate, trachea, uterus, small intestine, placenta, thyroid, salivary gland, and adrenal gland. Expression of TMCO4 is predicted to be controlled by many transcription factors.
# Clinical Significance
TMCO4 is not currently directly linked to any disease or phenotype. However, interacting with a VEGF receptor may be indicative of a possible role in cancer. | TMCO4
Transmembrane and coiled-coil domains 4, TMCO4, is a protein in humans that is encoded by the TMCO4 gene. Currently, its function is not well defined. It is transmembrane protein that is predicted to cross the endoplasmic reticulum membrane three times. TMCO4 interacts with other proteins known to play a role in cancer development, hinting at a possible role in the disease of cancer.
# Gene
TMCO4 is located on the minus strand of the first chromosome at 1p36.13.[2] The gene consists of 118,172 base pairs stretching from base pair 19,682,213 through 19,800,385.[2] There are no common aliases for TMCO4. Genes CAPZB and LOC105376823 neighbor TMCO4 on chromosome 1.[1] TMCO4 consists of 16 exons.[1]
# mRNA
There are twenty mRNA transcript variants (X1-X20) produced through different combinations of sixteen different exons.[3] The most common variant is X1, which includes all exons and spans the entire 118,172 base pairs.[1]
# Protein
## Primary sequence
The most common protein encoded by TMCO4 is 634 amino acids in length with accession number XP_011539488.1.[2]
## General properties and composition
The molecular weight of TMCO4 is 67.9 kiloDaltons. The isoelectric point is 5.48. As a whole protein, TMCO4 does not have abnormal amino acid distributions. It does have three long stretches of no charge that correspond with the location of the three different transmembrane regions. The first cytosolic domain of TMCO4 does have abnormally high amounts of leucine and glutamic acid and abnormally low amounts of asparagine. The larger lumenal domain of TMCO4 also has an abnormally low amount of asparagine and phenylalanine.
## Protein features
Two main areas of interest within the TMCO4 protein are the three transmembrane regions and the large Abhydrolase region.[4] The N-terminus of TMCO4 is predicted to be within the cytosol of the cell, and the C-terminus is predicted to be within the lumen of the endoplasmic retiticulum. TMCO4 is also predicted to have a leucine zipper and a large coiled coil domain.[5]
## Secondary structure
The secondary structure of TMCO4 is predicted to be dominated by alpha helices based on predictions by iTASSER software.[6]
## Post-translational modifications
Many phosphorylation sites were predicted for the two cytosolic regions of TMCO4.[7] O-linked glycosylation sites were predicted to occur in the end of the second lumenal region of TMCO4.[8] These predicted sites can be seen on both the schematic illustration of TMCO4 found above, or in the conceptual translation of TMCO4 found below.
## Subcellular localization
TMCO4 is consistently predicted to be located in the endoplasmic reticulum membrane across many homologs.[5]
## Interacting proteins
TMCO4 has been found to interact with many proteins. One protein of interest that TMCO4 interacts with is FLT1.[9] FLT1 is a VEGF receptor[10]. VEGF is known to play a significant role in cancer development. Other proteins that TMCO4 has been experimentally shown to interact with are UBB, UBC, KPTN, and BVLF1.[9] UBB and UBC are polyubiquitins that target molecules for degradation, suggesting that TMCO4 is degraded at some point.[11][12] KPTN is a protein that is essential in neuromorphogenesis.[13] BVLF1 is an Epstein-Barr virus protein.[14]
# Homology
## Paralogs
TMCO4 does not have any paralogs.
## Orthologs
Orthologs to TMCO4 can be found in bacteria, protists, plants, fungi, trichoplax, ivertebrates, fish, amphibians, reptiles, birds and mammals.[15] Some of these orthologs can be found in the table below.[15] The orthologs are sorted in descending order of date of evolution from humans and then descending order of percent sequence identity. TMCO4 is a fast evolving gene that has been highly conserved throughout evolution.[15] Regions of TMCO4 that are highly conserved across the orthologs include the various transmembrane domains and the abhydrolase region.
# Expression
TMCO4 is highly expressed in many tissues. Highest expression occurs within the prostate, trachea, uterus, small intestine, placenta, thyroid, salivary gland, and adrenal gland. Expression of TMCO4 is predicted to be controlled by many transcription factors.
# Clinical Significance
TMCO4 is not currently directly linked to any disease or phenotype. However, interacting with a VEGF receptor may be indicative of a possible role in cancer. | https://www.wikidoc.org/index.php/TMCO4 | |
ed05cc450f279a0926f2243ccac83bdf23d0258b | wikidoc | TMCO6 | TMCO6
Transmembrane and coiled-coil domain 6, TMCO6, is a protein that in humans is encoded by the TMCO6 gene with aliases of PRO1580, HQ1580 or FLJ39769.1.
# Gene
The human TMCO6 is found on chromosome 5 (position 5q31.3). The entire gene spans 5568 base pairs on the positive strand of chromosome 5 (140019113-140024689bp) but is alternately spliced into different variants. There are three known variants for TMCO6. Variant 1 is the longest and variant 2 and 3 are spliced into shorter mRNA strands. There is also a predicted variants X1-X7.
## Expression
TMCO6 is expressed in liver tissue and is found during the fetal stage of development in humans.
# Homology
Orthologs of the TMCO6 protein have been found among sequenced organisms with the exception of invertebrates, fungi, plants and bacteria. Tmco6 (transmembrane and coiled-coil domains 6) - Rat Genome Database. This includes close primates to some distant fish. Graphs show the evolutionary rate of TMCO6 with respect to different species and compared to other proteins. It is concluded that TMCO6 is a fairly fast evolving protein, similar to fibrinogen.
# Transcription
There are four known isoforms associated with this gene/protein (1, 2, 3 and X2). The longest variant of TMCO6 is variant 1, encoded by a 12-exon long, 1,925 base pair mRNA sequence. Variant 2 is the second longest at 1,907 base pairs in length and also consists of 12 exons. This transcript variant has an alternate splice site in the central coding region that does not alter the reading frame. Variant 3 has a total length of 1,614 base pairs and differs from variant 1 because it lacks two consecutive exons. It has an alternative splice site in the 5’ region that causes the translation to initiate downstream at an in frame AUG. Variant X2 is predicted using computational analysis and is 1,892 base pairs in length.
# Protein
The TMCO6 protein is found in the membrane and is considered a multi-pass membrane protein. There is evidence of its presence in the nucleus, cytosol, ER, mitochondria and the plasma membrane. The predicted molecular weight of Isoform 1 in humans, but is conserved, is 55kDa. Variant 1 is translated into a 499 amino acid sequence isoform. Isoform 2, encoded by transcript variant 2, is 493 amino acids in length and has a predicted molecular weight of 54 kDa. Transcript variant 3 encodes isoform 3 which is the shortest protein because of its spliced N-terminus. Isoform 3 is 253 amino acids in length with a molecular weight of 28kDa.
## Domains and motifs
Evidence of two reserved ARM superfamily domains are shown in the TMCO6 protein. The ARM domain, Armadillo/ beta-catenin-like-repeat, is about a 40 amino acid long tandem repeat that forms superhelix of helices. Another feature is that TMCO6 has an Arginine rich region that is within the coil-coiled region. This indicates that the Arg rich area might be an important structural feature of the coiled-coil region. There are 17 regions for protein binding, 2 transmembrane domains and an addition of a poly-A tail to the mRNA. An SRP1 is also found from the 23-399 amino acids. The SRP1 domain is Karyopherin(importin) alpha. This is involved in the exchange of molecules from the nucleus and the cytoplasm. The exchange involves the active transport by a carrier protein called karyopherins. A di-leucine motif is also abundant in TMCO6. This motif is commonly known to be a lysosome targeting motif. A nuclear localization sequence of 5 positive amino acids is found near the 5' end indicating its transport to the nucleus.
## Structure
The 5' and 3' end of TMCO6 is predicted to be located on the cytoplasmic side of the membrane. There is a small portion located in the non-cytoplasmic side.
# Function
Function of the conserved ARM domain and SRP1 domains are known. The ARM domains play a role in mediating the interaction of beta-catenin with its ligand. They are responsible for transduction of the Wnt signal, intracellular signaling and cytoskeletal regulation. The SRP1 domain encodes alpha-Karyopherin (importin) and is known for intracellular trafficking and secretion on the membrane. TMCO6 is thought to be involved in the transport of molecules through the nuclear membrane.
# Interactions
Two-hybrid experimental evidence suggests UBQLN1, or ubiquilin 1, has a high potential to interact with TMCO6. | TMCO6
Transmembrane and coiled-coil domain 6, TMCO6, is a protein that in humans is encoded by the TMCO6 gene with aliases of PRO1580, HQ1580 or FLJ39769.1.[1]
# Gene
The human TMCO6 is found on chromosome 5 (position 5q31.3).[2] The entire gene spans 5568 base pairs on the positive strand of chromosome 5 (140019113-140024689bp) but is alternately spliced into different variants. There are three known variants for TMCO6. Variant 1 is the longest and variant 2 and 3 are spliced into shorter mRNA strands.[3] There is also a predicted variants X1-X7.
## Expression
TMCO6 is expressed in liver tissue and is found during the fetal stage of development in humans.[3][4]
# Homology
Orthologs of the TMCO6 protein have been found among sequenced organisms with the exception of invertebrates, fungi, plants and bacteria.[1] Tmco6 (transmembrane and coiled-coil domains 6) - Rat Genome Database.[5] This includes close primates to some distant fish. Graphs show the evolutionary rate of TMCO6 with respect to different species and compared to other proteins. It is concluded that TMCO6 is a fairly fast evolving protein, similar to fibrinogen.
# Transcription
There are four known isoforms associated with this gene/protein (1, 2, 3 and X2).[3] The longest variant of TMCO6 is variant 1, encoded by a 12-exon long, 1,925 base pair mRNA sequence. Variant 2 is the second longest at 1,907 base pairs in length and also consists of 12 exons. This transcript variant has an alternate splice site in the central coding region that does not alter the reading frame. Variant 3 has a total length of 1,614 base pairs and differs from variant 1 because it lacks two consecutive exons. It has an alternative splice site in the 5’ region that causes the translation to initiate downstream at an in frame AUG. Variant X2 is predicted using computational analysis and is 1,892 base pairs in length.[3]
# Protein
The TMCO6 protein is found in the membrane and is considered a multi-pass membrane protein.[1] There is evidence of its presence in the nucleus, cytosol, ER, mitochondria and the plasma membrane.[1] The predicted molecular weight of Isoform 1 in humans, but is conserved, is 55kDa.[2] Variant 1 is translated into a 499 amino acid sequence isoform.[2][3] Isoform 2, encoded by transcript variant 2, is 493 amino acids in length and has a predicted molecular weight of 54 kDa. Transcript variant 3 encodes isoform 3 which is the shortest protein because of its spliced N-terminus. Isoform 3 is 253 amino acids in length with a molecular weight of 28kDa.
## Domains and motifs
Evidence of two reserved ARM superfamily domains are shown in the TMCO6 protein.[2] The ARM domain, Armadillo/ beta-catenin-like-repeat, is about a 40 amino acid long tandem repeat that forms superhelix of helices. Another feature is that TMCO6 has an Arginine rich region that is within the coil-coiled region.[6] This indicates that the Arg rich area might be an important structural feature of the coiled-coil region. There are 17 regions for protein binding, 2 transmembrane domains and an addition of a poly-A tail to the mRNA.[6] An SRP1 is also found from the 23-399 amino acids. The SRP1 domain is Karyopherin(importin) alpha.[6] This is involved in the exchange of molecules from the nucleus and the cytoplasm. The exchange involves the active transport by a carrier protein called karyopherins.[6] A di-leucine motif is also abundant in TMCO6. This motif is commonly known to be a lysosome targeting motif.[7] A nuclear localization sequence of 5 positive amino acids is found near the 5' end indicating its transport to the nucleus.
## Structure
The 5' and 3' end of TMCO6 is predicted to be located on the cytoplasmic side of the membrane. There is a small portion located in the non-cytoplasmic side.
# Function
Function of the conserved ARM domain and SRP1 domains are known.[2] The ARM domains play a role in mediating the interaction of beta-catenin with its ligand. They are responsible for transduction of the Wnt signal, intracellular signaling and cytoskeletal regulation. The SRP1 domain encodes alpha-Karyopherin (importin) and is known for intracellular trafficking and secretion on the membrane. TMCO6 is thought to be involved in the transport of molecules through the nuclear membrane.
# Interactions
Two-hybrid experimental evidence suggests UBQLN1, or ubiquilin 1, has a high potential to interact with TMCO6.[1][8] | https://www.wikidoc.org/index.php/TMCO6 | |
aa0c1cfad9d585eb29c398d897f604404f4520cd | wikidoc | TMLHE | TMLHE
Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X. Mutations in the TMLHE gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms.
# Structure
The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability, and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.
# Function
The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway, which is part of amine biosynthesis. Carnitine is a molecule that play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane where they are metabolized. The encoded protein converts trimethyllysine into hydroxytrimethyllysine with the reaction (EC 1.14.11.8):
N6,N6,N(6)-trimethyl-L-lysine + 2-oxoglutarate + O2 = 3-hydroxy-N6,N6,N(6)-trimethyl-L-lysine + succinate + CO2.
and requires iron and L-ascorbate as co-factors.
# Clinical significance
Mutations in the THLHE gene causes Epsilon-trimethyllysine hydroxylase deficiency (TMLHED), an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and Autism spectrum disorders.
# Interactions
THLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. THLHE appears to interact with SUGCT. | TMLHE
Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X.[1][2][3] Mutations in the TMLHE gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms.[4]
# Structure
The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability,[5] and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.[6]
# Function
The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway,[6] which is part of amine biosynthesis. Carnitine is a molecule that play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane where they are metabolized. The encoded protein converts trimethyllysine into hydroxytrimethyllysine with the reaction (EC 1.14.11.8):
N6,N6,N(6)-trimethyl-L-lysine + 2-oxoglutarate + O2 = 3-hydroxy-N6,N6,N(6)-trimethyl-L-lysine + succinate + CO2.
and requires iron and L-ascorbate as co-factors.
# Clinical significance
Mutations in the THLHE gene causes Epsilon-trimethyllysine hydroxylase deficiency (TMLHED),[7][8] an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and Autism spectrum disorders.[9][4]
# Interactions
THLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. THLHE appears to interact with SUGCT.[10] | https://www.wikidoc.org/index.php/TMLHE | |
859076ec8247508f0bc21535f4b9fdf147dbad59 | wikidoc | TMTC4 | TMTC4
Transmembrane and Tetratricopeptide repeat containing 4 is a protein that in humans is encoded by the TMTC4 gene. This protein crosses the plasma membrane 10 times, and resides in the ER lumen and cytosol. The predicted structure of the TMTC4 protein is a series of alpha-helices.
# Gene
TMTC4 is located on chromosome 13 at 13q32.3. The gene is flanked by ADP ribosylation factor 4 pseudogene 3 (ARF4P3) on the left, and ribosomal protein S26 pseudogene 47 (RPS26P47) on the right. TMTC4 spans 4043 bp and has a total of 23 exons.
# mRNA
TMTC4 has seven isoform variants, the most common being isoform 1 at 4043 bp.
The 5’ UTR for TMTC4 is short and in many of the shorter isoforms, portions of this untranslated region are cut. In comparison, the 3’ UTR is long and is often complete across the seven isoforms.
# Protein
## Physical properties
The molecular weight for TMTC4 is 85.0 kdal, and there are no positive, negative, or neutral clusters of amino acids or charge runs exceeding the normal lengths. When looking at a distant ortholog (purple sea urchin) the molecular weight of TMTC4 is 85.5 kdal and there, again, are no charge runs, positive, negative or neutral clusters, or unusual spacings. There are strong similarities in protein composition across species. The isoelectric point for the domain of unknown function (DUF 1736) is lower than that of the protein overall.
## Domains
TMTC4 has ten transmembrane regions, all of them spaced within the first half of the protein.
TMTC4 is layered with tetratricopeptide (TPR) repeat sequences that are a part of the TPR superfamily of proteins. DUF1736 is present upstream of the TPR region. A seven residue repeat (SRR) is located toward the end of the protein, and it is thought to encode a coiled-coil structure. Another member of the TPR family, PFTA (protein prenyltransferases alpha subunit repeat), is located within the protein’s TPR region and is believed to be involved in signal transduction and vesicular traffic regulation. LSPR coagulation factor V, also a repeat motif, is located within the TPR region, and is thought to be a central regulator of hemostasis.
## Secondary structure
TMTC4 takes on a series of alpha-helix structures, especially within the TPR region, though there are a minimal amount of beta-strand structures spaced throughout the beginning half of the protein.
## Post-translational modifications
There are four predicted nuclear localization signals, each tagging the protein for nuclear import. At the very end of the protein, however, there is a predicted ER retention signal which would prevent the protein from leaving the ER. The protein has three predicted N-glycosylation sites, potentially altering its structure and function and there are ten predicted phosphorylation sites, each a possible activation site for a regulatory mechanism.
# Expression
TMTC4 is expressed in all human tissues. The gene, however, is most highly expressed in the brain and in the spinal cord.
Protein abundance seems to be lower than normal for TMTC4.
## Regulation
There is one possible promoter for the TMTC4 gene, located in the 5’ UTR but before the start of the coding sequence.
# Function
Currently the function of TMTC4 has not been characterized.
# Interacting proteins
Possible interacting proteins are NRG1, PEX19, HERC3, TXNDC15, and COL1A1 . All of these were detected through affinity chromatography.
# Homology
## Orthologs
Ortholog space for TMTC4 spans a large portion of evolutionary time. TMTC4 is present in mammals, reptiles, amphibians, birds, fish, and invertebrates. It is not present in plants, bacteria, archaea, or fungi.
## Paralogs
Paralog space for TMTC4 spans the gene family TMTC. There are four genes in this gene family: TMTC1, TMTC2, TMTC3, and TMTC4. TMTC1 and TMTC3 split from TMTC4 about 1200 million years ago, while TMTC2 split from TMTC4 1400 million years ago. Both of these events happened somewhere between invertebrates and plants. | TMTC4
Transmembrane and Tetratricopeptide repeat containing 4 is a protein that in humans is encoded by the TMTC4 gene.[1] This protein crosses the plasma membrane 10 times, and resides in the ER lumen and cytosol. The predicted structure of the TMTC4 protein is a series of alpha-helices.
# Gene
TMTC4 is located on chromosome 13 at 13q32.3. The gene is flanked by ADP ribosylation factor 4 pseudogene 3 (ARF4P3) on the left, and ribosomal protein S26 pseudogene 47 (RPS26P47) on the right. TMTC4 spans 4043 bp and has a total of 23 exons.[1]
# mRNA
TMTC4 has seven isoform variants, the most common being isoform 1 at 4043 bp.[1]
The 5’ UTR for TMTC4 is short and in many of the shorter isoforms, portions of this untranslated region are cut. In comparison, the 3’ UTR is long and is often complete across the seven isoforms.
# Protein
## Physical properties
The molecular weight for TMTC4 is 85.0 kdal, and there are no positive, negative, or neutral clusters of amino acids or charge runs exceeding the normal lengths. When looking at a distant ortholog (purple sea urchin) the molecular weight of TMTC4 is 85.5 kdal and there, again, are no charge runs, positive, negative or neutral clusters, or unusual spacings. There are strong similarities in protein composition across species. The isoelectric point for the domain of unknown function (DUF 1736) is lower than that of the protein overall.
## Domains
TMTC4 has ten transmembrane regions, all of them spaced within the first half of the protein.[2]
TMTC4 is layered with tetratricopeptide (TPR) repeat sequences that are a part of the TPR superfamily of proteins. DUF1736 is present upstream of the TPR region. A seven residue repeat (SRR) is located toward the end of the protein, and it is thought to encode a coiled-coil structure.[3] Another member of the TPR family, PFTA (protein prenyltransferases alpha subunit repeat), is located within the protein’s TPR region and is believed to be involved in signal transduction and vesicular traffic regulation.[4] LSPR coagulation factor V, also a repeat motif, is located within the TPR region, and is thought to be a central regulator of hemostasis.[5]
## Secondary structure
TMTC4 takes on a series of alpha-helix structures, especially within the TPR region, though there are a minimal amount of beta-strand structures spaced throughout the beginning half of the protein.[6]
## Post-translational modifications
There are four predicted nuclear localization signals, each tagging the protein for nuclear import.[2] At the very end of the protein, however, there is a predicted ER retention signal which would prevent the protein from leaving the ER. The protein has three predicted N-glycosylation sites, potentially altering its structure and function and there are ten predicted phosphorylation sites, each a possible activation site for a regulatory mechanism.[2]
# Expression
TMTC4 is expressed in all human tissues. The gene, however, is most highly expressed in the brain and in the spinal cord.[7]
Protein abundance seems to be lower than normal for TMTC4.
## Regulation
There is one possible promoter for the TMTC4 gene, located in the 5’ UTR but before the start of the coding sequence.
# Function
Currently the function of TMTC4 has not been characterized.
# Interacting proteins
Possible interacting proteins are NRG1, PEX19, HERC3, TXNDC15, and COL1A1 . All of these were detected through affinity chromatography.[8]
# Homology
## Orthologs
Ortholog space for TMTC4 spans a large portion of evolutionary time. TMTC4 is present in mammals, reptiles, amphibians, birds, fish, and invertebrates. It is not present in plants, bacteria, archaea, or fungi.[13]
## Paralogs
Paralog space for TMTC4 spans the gene family TMTC. There are four genes in this gene family: TMTC1, TMTC2, TMTC3, and TMTC4. TMTC1 and TMTC3 split from TMTC4 about 1200 million years ago, while TMTC2 split from TMTC4 1400 million years ago. Both of these events happened somewhere between invertebrates and plants. | https://www.wikidoc.org/index.php/TMTC4 | |
980ca89c5a27690feda07abb36bceefe57c4d0f8 | wikidoc | TNNI1 | TNNI1
Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene. It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.
Gene TNNI1, troponin I type 1 (skeletal muscle, slow), also known as TNN1 and SSTNI, is located at 1q31.3 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin I (ssTnI), the inhibitory subunit of the troponin complex in striated muscle myofilaments. Human TNNI1 spans 12.5 kilobases in the genomic DNA and contains 9 exons and 8 introns. Exon 2 to exon 8 contain the coding sequences, encoding a protein of 21.7 kDa consisting of 187 amino acids including the first methionine with an isoelectric point (pI) of 9.59.
# Gene evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI. In mammals, the amino acid sequence of ssTnI is highly conserved. Mouse and bovine ssTnI each differs from human ssTnI in only four amino acids, and rhesus monkey ssTnI is identical to human in the amino acid sequences. In lower vertebrates, the divergence of ssTnI between species is larger than that in the higher vertebrates (Fig1).
# Tissue distribution
Comparing with the fast twitch skeletal muscle and cardiac TnI isoform genes (TNNT2 and TNNT3), TNNI1 has a broader range of expression in avian and mammalian striated muscles. It is the predominant TnI isoform expressed in both slow skeletal muscle and cardiac muscle in early embryonic stage. An isoform switch from ssTnI to cTnI occurs during perinatal heart development. ssTnI is not expressed in the embryonic hearts of Xenopus and zebrafish, while it is expressed in the somites and skeletal muscles.
# Structure-function relationships
The function of TnI is to control striated muscle contraction and relaxation. Troponin I interacts with all major regulatory proteins in the sarcomeric thin filaments of cardiac and skeletal muscles: troponin C, troponin T, tropomyosin and actin. When cytosolic Ca2+ is low, TnI binds the thin filament to block the myosin binding sites on actin. The rise of cytosolic Ca2+ results in binding to the N-terminal domain of troponin C and induces conformational changes in troponin C and the troponin complex, which releases the inhibition of myosin-actin interaction and activates myosin ATPase and cross bridge cycling to generate myosin power strokes and muscle contraction.
To date, no high resolution structure of ssTnI has been solved. As homologous proteins, ssTnI, fast skeletal muscle TnI and cardiac TnI have highly conserved structures and crystallographic high resolution structure of partial cardiac and fast skeletal troponin complex are both available. Therefore, the structure-function relationship of ssTnI would rely on the information from studies performed on fast skeletal muscle and cardiac TnI.
# Posttranslational modifications
To date, no posttranslational modification of ssTnI has been identified.
# Mutations
To date, no human disease has been reported with mutations in TNNI1.
# Clinical significance
Slow to fast skeletal TnI isoform switch occurs as an indicator for slow to fast fiber type transition in muscle adaptations. Slow skeletal TnI has been proposed as a sensitive and muscle fiber type-specific marker for skeletal muscle injuries. In patients with skeletal muscle disorders, intact ssTnI or its degraded products may be detected in peripheral blood as a diagnostic indicator for slow fiber damages.
# Notes | TNNI1
Troponin I, slow skeletal muscle is a protein that in humans is encoded by the TNNI1 gene.[1][2][3] It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.
Gene TNNI1, troponin I type 1 (skeletal muscle, slow), also known as TNN1 and SSTNI, is located at 1q31.3 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin I (ssTnI), the inhibitory subunit of the troponin complex in striated muscle myofilaments.[4][5] Human TNNI1 spans 12.5 kilobases in the genomic DNA and contains 9 exons and 8 introns.[6] Exon 2 to exon 8 contain the coding sequences, encoding a protein of 21.7 kDa consisting of 187 amino acids including the first methionine with an isoelectric point (pI) of 9.59.
# Gene evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI.[4][7][8] In mammals, the amino acid sequence of ssTnI is highly conserved. Mouse and bovine ssTnI each differs from human ssTnI in only four amino acids, and rhesus monkey ssTnI is identical to human in the amino acid sequences. In lower vertebrates, the divergence of ssTnI between species is larger than that in the higher vertebrates (Fig1).
# Tissue distribution
Comparing with the fast twitch skeletal muscle and cardiac TnI isoform genes (TNNT2 and TNNT3), TNNI1 has a broader range of expression in avian and mammalian striated muscles. It is the predominant TnI isoform expressed in both slow skeletal muscle and cardiac muscle in early embryonic stage.[9] An isoform switch from ssTnI to cTnI occurs during perinatal heart development.[9][10][11] ssTnI is not expressed in the embryonic hearts of Xenopus and zebrafish, while it is expressed in the somites and skeletal muscles.[12][13]
# Structure-function relationships
The function of TnI is to control striated muscle contraction and relaxation. Troponin I interacts with all major regulatory proteins in the sarcomeric thin filaments of cardiac and skeletal muscles: troponin C, troponin T, tropomyosin and actin. When cytosolic Ca2+ is low, TnI binds the thin filament to block the myosin binding sites on actin. The rise of cytosolic Ca2+ results in binding to the N-terminal domain of troponin C and induces conformational changes in troponin C and the troponin complex, which releases the inhibition of myosin-actin interaction and activates myosin ATPase and cross bridge cycling to generate myosin power strokes and muscle contraction.
To date, no high resolution structure of ssTnI has been solved. As homologous proteins, ssTnI, fast skeletal muscle TnI and cardiac TnI have highly conserved structures and crystallographic high resolution structure of partial cardiac and fast skeletal troponin complex are both available. Therefore, the structure-function relationship of ssTnI would rely on the information from studies performed on fast skeletal muscle and cardiac TnI.
# Posttranslational modifications
To date, no posttranslational modification of ssTnI has been identified.
# Mutations
To date, no human disease has been reported with mutations in TNNI1.
# Clinical significance
Slow to fast skeletal TnI isoform switch occurs as an indicator for slow to fast fiber type transition in muscle adaptations.[14] Slow skeletal TnI has been proposed as a sensitive and muscle fiber type-specific marker for skeletal muscle injuries.[15][16] In patients with skeletal muscle disorders, intact ssTnI or its degraded products may be detected in peripheral blood as a diagnostic indicator for slow fiber damages.
# Notes | https://www.wikidoc.org/index.php/TNNI1 | |
e09f484839a584f0391bf3ecd00231b7feef7349 | wikidoc | TNNI2 | TNNI2
Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene.
The TNNI2 gene is located at 11p15.5 in the human chromosomal genome, encoding the fast twitch skeletal muscle troponin I (fsTnI). fsTnI is a 21.3 kDa protein consisting of 182 amino acids including the first methionine with an isoelectric point (pI) of 8.74. It is the inhibitory subunit of the troponin complex in fast twitch skeletal muscle fibers.
# Gene evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI. Sequence analysis, immunological distance, and examination of evolutionarily suppressed conformational states showed that the TnI genes have evolved in close linkage with the genes encoding troponin T (TnT), another subunit of the troponin complex. The fast TnI-fast TnT gene pair represents the original TnI and TnT genes (Fig. 1). The three muscle fiber type-specific TnI-TnT gene pairs were likely originated from a TnI-like ancestor gene that presumably duplicated to form a closely linked fast TnI-like and fast TnT-like gene pair. A later duplication events resulted in emergences of a slow TnI-like and cardiac TnT-like gene pair that was further duplicated to give rise of the present-day slow TnI-cardiac TnT and cardiac TnI-slow TnT gene pairs. The seemingly scrambled ssTnI and cTnI gene pair is actually functionally related as they co-express and form troponin complex in the embryonic heart. The overlapping of enhancer elements of the TnT gene promoter with the upstream TnI gene structure may be a critical factor in the preservation of the close linkage of TnI and TnT gene pairs
The phylogenetic tree in Fig. 2 summarizes the evolutionary lineage of fsTnI isoforms in vertebrate species.
Phylogenetic analysis of vertebrate TnI isoforms demonstrated that each of the muscle type-specific isoforms is more conserved across species than the three isoforms in one given species, indicating early diverged functions of the muscle fiber type-specific isoforms as well as the conservation of functions for each muscle fiber type.
# Tissue distribution
Fast skeletal muscle TnI was first cloned from a skeletal muscle cDNA library. It is generally observed that fsTnI is exclusively expressed in fast twitch skeletal muscle fibers. More recent studies reported that subunits of fast skeletal muscle troponin (fsTnI, fsTnT, fsTnC) were expressed at significant levels in smooth muscle cells of mouse blood vessels, bladder and bronchi. Expression of fsTnI was also found in non-muscle cells, such as human corneal epithelial cells and cartilage. The function of fsTnI expressed in smooth muscle and non-muscle cells is unclear.
# Protein structure and function
Crystallographic structure of fsTnI in troponin complex from chicken fast skeletal muscle showed an overall structure similar to that of cardiac troponin. The inhibitory region of fsTnI was resolved in skeletal troponin whereas it was invisible in the cardiac troponin crystal structure. Based on the crystal structure, a schematic illustration (Fig. 3) was proposed to show the conformational changes in troponin during muscle activation and relaxation.
## Posttranslational modifications
Phosphorylation: Ser118 of fsTnI, equivalent to Ser150 in cTnI, was reported as a phosphorylation substrate of AMPK. As AMPK is a key regulator of cellular energetics, phosphorylation of this site may provide an adaptive mechanism during energy deprivation in both skeletal and cardiac muscles.
S-glutathionylation: fsTnI was found to be S-glutathionylated at Cys133 in rodent fast-twitch skeletal muscle and in human type II muscle fibers after exercise, which increased Ca2+ sensitivity of the contractile apparatus.
# Clinical significance
A missense mutation R174Q, a nonsense mutation R156X, and three single residue deletions DE167, DK175 and DK176, all in the C-terminal actin-tropomyosin interacting domain, have been found in patients with distal arthrogryposis.
Skeletal muscle TnI has been proposed as a sensitive and fast fiber-specific serum marker of skeletal muscle injury. fsTnI concentration in increased peripheral blood when fast twitch fibers were damaged.
# Notes | TNNI2
Troponin I, fast skeletal muscle is a protein that in humans is encoded by the TNNI2 gene.[1][2]
The TNNI2 gene is located at 11p15.5 in the human chromosomal genome, encoding the fast twitch skeletal muscle troponin I (fsTnI). fsTnI is a 21.3 kDa protein consisting of 182 amino acids including the first methionine with an isoelectric point (pI) of 8.74. It is the inhibitory subunit of the troponin complex in fast twitch skeletal muscle fibers.[3]
# Gene evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type-specific isoforms of TnI.[4][5][6] Sequence analysis, immunological distance, and examination of evolutionarily suppressed conformational states showed that the TnI genes have evolved in close linkage with the genes encoding troponin T (TnT), another subunit of the troponin complex.[6] The fast TnI-fast TnT gene pair represents the original TnI and TnT genes (Fig. 1). The three muscle fiber type-specific TnI-TnT gene pairs were likely originated from a TnI-like ancestor gene that presumably duplicated to form a closely linked fast TnI-like and fast TnT-like gene pair. A later duplication events resulted in emergences of a slow TnI-like and cardiac TnT-like gene pair that was further duplicated to give rise of the present-day slow TnI-cardiac TnT and cardiac TnI-slow TnT gene pairs. The seemingly scrambled ssTnI and cTnI gene pair is actually functionally related as they co-express and form troponin complex in the embryonic heart. The overlapping of enhancer elements of the TnT gene promoter with the upstream TnI gene structure may be a critical factor in the preservation of the close linkage of TnI and TnT gene pairs[7]
The phylogenetic tree in Fig. 2 summarizes the evolutionary lineage of fsTnI isoforms in vertebrate species.
Phylogenetic analysis of vertebrate TnI isoforms demonstrated that each of the muscle type-specific isoforms is more conserved across species than the three isoforms in one given species, indicating early diverged functions of the muscle fiber type-specific isoforms as well as the conservation of functions for each muscle fiber type.[8]
# Tissue distribution
Fast skeletal muscle TnI was first cloned from a skeletal muscle cDNA library.[9] It is generally observed that fsTnI is exclusively expressed in fast twitch skeletal muscle fibers. More recent studies reported that subunits of fast skeletal muscle troponin (fsTnI, fsTnT, fsTnC) were expressed at significant levels in smooth muscle cells of mouse blood vessels,[10] bladder and bronchi.[11] Expression of fsTnI was also found in non-muscle cells, such as human corneal epithelial cells[12] and cartilage.[13][14] The function of fsTnI expressed in smooth muscle and non-muscle cells is unclear.
# Protein structure and function
Crystallographic structure of fsTnI in troponin complex from chicken fast skeletal muscle showed an overall structure[15] similar to that of cardiac troponin.[16] The inhibitory region of fsTnI was resolved in skeletal troponin whereas it was invisible in the cardiac troponin crystal structure. Based on the crystal structure, a schematic illustration (Fig. 3) was proposed to show the conformational changes in troponin during muscle activation and relaxation.
## Posttranslational modifications
Phosphorylation: Ser118 of fsTnI, equivalent to Ser150 in cTnI, was reported as a phosphorylation substrate of AMPK.[17] As AMPK is a key regulator of cellular energetics, phosphorylation of this site may provide an adaptive mechanism during energy deprivation in both skeletal and cardiac muscles.
S-glutathionylation: fsTnI was found to be S-glutathionylated at Cys133 in rodent fast-twitch skeletal muscle and in human type II muscle fibers after exercise, which increased Ca2+ sensitivity of the contractile apparatus.[18]
# Clinical significance
A missense mutation R174Q, a nonsense mutation R156X, and three single residue deletions DE167, DK175 and DK176, all in the C-terminal actin-tropomyosin interacting domain, have been found in patients with distal arthrogryposis.[19][20][21][22]
Skeletal muscle TnI has been proposed as a sensitive and fast fiber-specific serum marker of skeletal muscle injury.[23][24] fsTnI concentration in increased peripheral blood when fast twitch fibers were damaged.[24]
# Notes | https://www.wikidoc.org/index.php/TNNI2 | |
2a19d53089d8aa71cecea9a45578ba0ce152a6d3 | wikidoc | TNNI3 | TNNI3
Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene.
It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.
The TNNI3 gene encoding cardiac troponin I (cTnI) is located at 19q13.4 in the human chromosomal genome. Human cTnI is a 24 kDa protein consisting of 210 amino acids with isoelectric point (pI) of 9.87. cTnI is exclusively expressed in adult cardiac muscle.
# Gene evolution
cTnI has diverged from the skeletal muscle isoforms of TnI (slow TnI and fast TnI) mainly with a unique N-terminal extension. The amino acid sequence of cTnI is strongly conserved among mammalian species (Fig. 1). On the other hand, the N-terminal extension of cTnI has significantly different structures among mammal, amphibian and fish.
# Tissue distribution
TNNI3 is expressed as a heart specific gene. Early embryonic heart expresses solely slow skeletal muscle TnI. cTnI begins to express in mouse heart at approximately embryonic day 10, and the level gradually increases to one-half of the total amount of TnI in the cardiac muscle at birth. cTnI completely replaces slow TnI in the mouse heart approximately 14 days after birth
# Protein structure
Based on in vitro
structure-function relationship studies, the structure of cTnI can be divided into six functional segments: a) a cardiac-specific N-terminal extension (residue 1–30) that is not present in fast TnI and slow TnI; b)
an N-terminal region (residue 42–79) that binds the C domain of TnC; c) a TnT-binding region (residue 80–136); d) the inhibitory peptide (residue 128–147) that interacts with TnC and actin–tropomyosin; e) the switch or triggering region (residue 148–163) that binds the N domain of TnC; and f) the C-terminal mobile domain (residue 164–210) that binds actin–tropomyosin and is the most conserved segment highly similar among isoforms and across species. Partially crystal structure of human troponin has been determined.
## Posttranslational modifications
- Phosphorylation: cTnI was the first sarcomeric protein identified to be a substrate of PKA. Phosphorylation of cTnI at Ser23/Ser24 under adrenergic stimulation enhances relaxation of cardiac muscle, which is critical to cardiac function especially at fast heart rate. Whereas PKA phosphorylation of Ser23/Ser24 decreases myofilament Ca2+ sensitivity and increases relaxation, phosphorylation of Ser42/Ser44 by PKC increases Ca2+ sensitivity and decreases cardiac muscle relaxation. Ser5/Ser6, Tyr26, Thr31, Ser39, Thr51, Ser77, Thr78, Thr129, Thr143 and Ser150 are also phosphorylation sites in human cTnI.
- O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction. Mass spectrometry identified Ser150 of mouse cTnI as an O-GlcNAcylation site, suggesting a potential role in regulating myocardial contractility.
- C-terminal truncation: The C-terminal end segment is the most conserved region of TnI. As an allosteric structure regulated by Ca2+ in the troponin complex, it binds and stabilizes the position of tropomyosin in low Ca2+ state implicating a role in the inhibition of actomyosin ATPase. A deletion of the C-terminal 19 amino acids was found during myocardial ischemia-reperfusion injury in Langendorff perfused rat hearts. It was also seen in myocardial stunning in coronary bypass patients. Over-expression of the C-terminal truncated cardiac TnI (cTnI1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions. Replacement of intact cTnI with cTnT1-192 in myofibrils and cardiomyocytes did not affect maximal tension development but decreased the rates of force redevelopment and relaxation.
- Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure. The N-terminal extension contains the PKA phosphorylation sites Ser23/Ser24 and plays a role in modulating the overall molecular conformation and function of cTnI. A restrictive N-terminal truncation of cTnI occurs at low levels in normal hearts of all vertebrate species examined including human and significantly increases in adaptation to hemodynamic stress and Gsα deficiency-caused failing mouse hearts. Distinct from the harmful C-terminal truncation, the restrictive N-terminal truncation of cTnI selectively removing the adult heart specific extension forms a regulatory mechanism in cardiac adaptation to physiological and pathological stress conditions.
# Pathologic mutations
Multiple mutations in cTnI have been found to cause cardiomyopathies. cTnI mutations account for approximately 5% of familial hypertrophic cardiomyopathy cases and to date, more than 20 myopathic mutations of cTnI have been characterized.
# Clinical implications
The half-life of cTnI in adult cardiomyocytes is estimated to be ~3.2 days and there is a pool of unassembled cardiac TnI in the cytoplasm. Cardiac TnI is exclusively expressed in the myocardium and is thus a highly specific diagnostic marker for cardiac muscle injuries, and cTnI has been universally used as indicator for myocardial infarction. An increased level of serum cTnI also independently predicts poor prognosis of critically ill patients in the absence of acute coronary syndrome.
# Notes | TNNI3
Troponin I, cardiac muscle is a protein that in humans is encoded by the TNNI3 gene.[1][2]
It is a tissue-specific subtype of troponin I, which in turn is a part of the troponin complex.
The TNNI3 gene encoding cardiac troponin I (cTnI) is located at 19q13.4 in the human chromosomal genome. Human cTnI is a 24 kDa protein consisting of 210 amino acids with isoelectric point (pI) of 9.87. cTnI is exclusively expressed in adult cardiac muscle.[3][4]
# Gene evolution
cTnI has diverged from the skeletal muscle isoforms of TnI (slow TnI and fast TnI) mainly with a unique N-terminal extension. The amino acid sequence of cTnI is strongly conserved among mammalian species (Fig. 1). On the other hand, the N-terminal extension of cTnI has significantly different structures among mammal, amphibian and fish.[4]
# Tissue distribution
TNNI3 is expressed as a heart specific gene.[4] Early embryonic heart expresses solely slow skeletal muscle TnI. cTnI begins to express in mouse heart at approximately embryonic day 10, and the level gradually increases to one-half of the total amount of TnI in the cardiac muscle at birth.[5] cTnI completely replaces slow TnI in the mouse heart approximately 14 days after birth [6]
# Protein structure
Based on in vitro
structure-function relationship studies, the structure of cTnI can be divided into six functional segments:[7] a) a cardiac-specific N-terminal extension (residue 1–30) that is not present in fast TnI and slow TnI; b)
an N-terminal region (residue 42–79) that binds the C domain of TnC; c) a TnT-binding region (residue 80–136); d) the inhibitory peptide (residue 128–147) that interacts with TnC and actin–tropomyosin; e) the switch or triggering region (residue 148–163) that binds the N domain of TnC; and f) the C-terminal mobile domain (residue 164–210) that binds actin–tropomyosin and is the most conserved segment highly similar among isoforms and across species. Partially crystal structure of human troponin has been determined.[8]
## Posttranslational modifications
- Phosphorylation: cTnI was the first sarcomeric protein identified to be a substrate of PKA.[9] Phosphorylation of cTnI at Ser23/Ser24 under adrenergic stimulation enhances relaxation of cardiac muscle, which is critical to cardiac function especially at fast heart rate. Whereas PKA phosphorylation of Ser23/Ser24 decreases myofilament Ca2+ sensitivity and increases relaxation, phosphorylation of Ser42/Ser44 by PKC increases Ca2+ sensitivity and decreases cardiac muscle relaxation.[10] Ser5/Ser6, Tyr26, Thr31, Ser39, Thr51, Ser77, Thr78, Thr129, Thr143 and Ser150 are also phosphorylation sites in human cTnI.[11]
- O-linked GlcNAc modification: Studies on isolated cardiomyocytes found increased levels of O-GlcNAcylation of cardiac proteins in hearts with diabetic dysfunction.[12] Mass spectrometry identified Ser150 of mouse cTnI as an O-GlcNAcylation site, suggesting a potential role in regulating myocardial contractility.
- C-terminal truncation: The C-terminal end segment is the most conserved region of TnI.[13] As an allosteric structure regulated by Ca2+ in the troponin complex,[13][14][15] it binds and stabilizes the position of tropomyosin in low Ca2+ state[14][16] implicating a role in the inhibition of actomyosin ATPase. A deletion of the C-terminal 19 amino acids was found during myocardial ischemia-reperfusion injury in Langendorff perfused rat hearts.[17] It was also seen in myocardial stunning in coronary bypass patients.[18] Over-expression of the C-terminal truncated cardiac TnI (cTnI1-192) in transgenic mouse heart resulted in a phenotype of myocardial stunning with systolic and diastolic dysfunctions.[19] Replacement of intact cTnI with cTnT1-192 in myofibrils and cardiomyocytes did not affect maximal tension development but decreased the rates of force redevelopment and relaxation.[20]
- Restrictive N-terminal truncation: The approximately 30 amino acids N-terminal extension of cTnI is an adult heart-specific structure.[21][22] The N-terminal extension contains the PKA phosphorylation sites Ser23/Ser24 and plays a role in modulating the overall molecular conformation and function of cTnI.[23] A restrictive N-terminal truncation of cTnI occurs at low levels in normal hearts of all vertebrate species examined including human and significantly increases in adaptation to hemodynamic stress[24] and Gsα deficiency-caused failing mouse hearts.[25] Distinct from the harmful C-terminal truncation, the restrictive N-terminal truncation of cTnI selectively removing the adult heart specific extension forms a regulatory mechanism in cardiac adaptation to physiological and pathological stress conditions.[26]
# Pathologic mutations
Multiple mutations in cTnI have been found to cause cardiomyopathies.[27][28] cTnI mutations account for approximately 5% of familial hypertrophic cardiomyopathy cases and to date, more than 20 myopathic mutations of cTnI have been characterized.[11]
# Clinical implications
The half-life of cTnI in adult cardiomyocytes is estimated to be ~3.2 days and there is a pool of unassembled cardiac TnI in the cytoplasm.[29] Cardiac TnI is exclusively expressed in the myocardium and is thus a highly specific diagnostic marker for cardiac muscle injuries, and cTnI has been universally used as indicator for myocardial infarction.[30] An increased level of serum cTnI also independently predicts poor prognosis of critically ill patients in the absence of acute coronary syndrome.[31][32]
# Notes | https://www.wikidoc.org/index.php/TNNI3 | |
eb2c3401b5923a212253b3dc4e2a371717f9ab22 | wikidoc | TNNT1 | TNNT1
Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.
The TNNT1 gene is located at 19q13.4 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin T (ssTnT). ssTnT is an ~32-kDa protein consisting of 262 amino acids (including the first methionine) with an isoelectric point (pI) of 5.95. It is the tropomyosin binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of slow twitch skeletal muscle fibers. TNNT1 gene is specifically expressed in slow skeletal muscle of vertebrates, with one exception that dry land toad (Bufo) cardiac muscle expresses ssTnT other than cardiac TnT.
# Evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type specific isoforms of TnT. Each of the TnT isoform genes is linked to one of the three troponin I isoform genes encoding the inhibitory subunit of the troponin complex, in chromosomal DNA to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, ssTnI-cardiac (cTnT) and cTnI-ssTnT gene pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type specific TnT and TnI isoforms may have evolved from duplications of a fsTnI-like-fsTnT-like gene pair. Evolutionary lineage of the three TnI-TnT gene pairs shows that cTnI-ssTnT is the newest and most closely linked.
Protein sequence alignment demonstrated that TNNT1 genes are highly conserved among vertebrate species (Fig. 2), especially in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged among vertebrate species.
# Alternative splicing
In mammalian and avian species, TNNT1 gene has a total of 14 exons, among which exon 5 encoding an 11-amino acid in the N-terminal region is alternatively spliced, generating a high molecular weight and a low molecular weight slow TnT splice forms (Jin, Chen et al. 1998). Biochemical studies showed that TnT splice forms have detectable different molecular conformation in the middle and C-terminal regions, producing different binding affinities for TnI and tropomyosin. The alternative splice forms of ssTnT play a role in skeletal muscle adaptation in physiologic and pathological conditions. Alternative splicing at alternative acceptor sites of intron 5 generates a single amino acid difference in the N-terminal region of ssTnT, of which functional significance has not been established.
# Clinical significance
A nonsense mutation E180X in the exon 11 of TNNT1 gene causes Amish Nemaline Myopathy (ANM), which is a severe form of recessive nemaline myopathy originally found in the Old Order Amish population in Pennsylvania, USA. Truncation of the ssTnT polypeptide chain by the E180X mutation deletes the tropomyosin-binding site 2 as well as the binding sites for TnI and troponin C (TnC) in the C-terminal region (Fig. 3). Consistent with the recessive phenotype, the truncated ssTnT is incapable of incorporation into the myofilaments and completely degraded in muscle cells.
Tnnt1 gene targeted mouse studies reproduced the myopathic phenotypes of ANM. ssTnT null mice showed significantly decreased type I slow fibers in diaphragm and soleus muscles with hypertrophy of type II fast fibers, increased fatigability, and active regeneration of slow fibers (Wei, Lu et al. 2014).
Recent case reports identified three more mutations in TNNT1 gene to cause nemaline myopathies outside the Amish population. A nonsense mutation S108X in exon 9 was identified in a Hispanic male patient with severe recessive nemaline myopathy phenotype. A Dutch patient with compound heterozygous TNNT1 gene mutations that cause exon 8 and exon 14 deletions also presents nemaline myopathy phenotypes. A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) leading to aberrant splicing that causes C-terminal truncation of the protein (L203 truncation) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline Myopathy.
Illustrated in Fig. 3, the S108X mutation truncates ssTnT protein to cause a loss of functional structures equivalent to that of E180X. The exon 8 deletion destructs the middle region tropomyosin-binding site 1. The L203 truncation deletes the binding sites for TnI and TnC but preserves both tropomyosin-binding sites 1 and 2. It remains to be invistigated whether this novel mutation is able to bind the actin-tropomyosin thin filament in vivo and how it causes recessive nemaline myopathy.
Alternative splicing of exon 5 produces high and low molecular weight splice forms of ssTnT. The low molecular ssTnT was significantly upregulated in type 1 (demyelination) but not type 2 (axon loss) Charcot-Marie-Tooth disease, suggesting that structural modification of TnT in the myofilaments may contribute to adaptation to abnormalities in neuronal activation.
# Interactions
TNNT1 has been shown to interact with PRKG1.
# Notes | TNNT1
Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.[1][2]
The TNNT1 gene is located at 19q13.4 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin T (ssTnT). ssTnT is an ~32-kDa protein consisting of 262 amino acids (including the first methionine) with an isoelectric point (pI) of 5.95. It is the tropomyosin binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of slow twitch skeletal muscle fibers.[3][4][5] TNNT1 gene is specifically expressed in slow skeletal muscle of vertebrates, with one exception that dry land toad (Bufo) cardiac muscle expresses ssTnT other than cardiac TnT.[6]
# Evolution
Three homologous genes have evolved in vertebrates, encoding three muscle type specific isoforms of TnT.[5] Each of the TnT isoform genes is linked to one of the three troponin I[7] isoform genes encoding the inhibitory subunit of the troponin complex, in chromosomal DNA to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, ssTnI-cardiac (cTnT) and cTnI-ssTnT gene pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type specific TnT and TnI isoforms may have evolved from duplications of a fsTnI-like-fsTnT-like gene pair.[8] Evolutionary lineage of the three TnI-TnT gene pairs shows that cTnI-ssTnT is the newest[8] and most closely linked.[9]
Protein sequence alignment demonstrated that TNNT1 genes are highly conserved among vertebrate species (Fig. 2), especially in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged among vertebrate species.[4][5]
# Alternative splicing
In mammalian and avian species, TNNT1 gene has a total of 14 exons, among which exon 5 encoding an 11-amino acid in the N-terminal region is alternatively spliced, generating a high molecular weight and a low molecular weight slow TnT splice forms (Jin, Chen et al. 1998).[10][11] Biochemical studies showed that TnT splice forms have detectable different molecular conformation in the middle and C-terminal regions, producing different binding affinities for TnI and tropomyosin.[4][5] The alternative splice forms of ssTnT play a role in skeletal muscle adaptation in physiologic and pathological conditions.[12] Alternative splicing at alternative acceptor sites of intron 5 generates a single amino acid difference in the N-terminal region of ssTnT,[11] of which functional significance has not been established.
# Clinical significance
A nonsense mutation E180X in the exon 11 of TNNT1 gene causes Amish Nemaline Myopathy (ANM), which is a severe form of recessive nemaline myopathy originally found in the Old Order Amish population in Pennsylvania, USA.[13][14] Truncation of the ssTnT polypeptide chain by the E180X mutation deletes the tropomyosin-binding site 2[15] as well as the binding sites for TnI and troponin C (TnC) in the C-terminal region (Fig. 3). Consistent with the recessive phenotype, the truncated ssTnT is incapable of incorporation into the myofilaments and completely degraded in muscle cells.[16]
Tnnt1 gene targeted mouse studies reproduced the myopathic phenotypes of ANM.[17][18] ssTnT null mice showed significantly decreased type I slow fibers in diaphragm and soleus muscles with hypertrophy of type II fast fibers, increased fatigability, and active regeneration of slow fibers (Wei, Lu et al. 2014).[17]
Recent case reports identified three more mutations in TNNT1 gene to cause nemaline myopathies outside the Amish population. A nonsense mutation S108X in exon 9 was identified in a Hispanic male patient with severe recessive nemaline myopathy phenotype.[19] A Dutch patient with compound heterozygous TNNT1 gene mutations that cause exon 8 and exon 14 deletions also presents nemaline myopathy phenotypes.[20] A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) leading to aberrant splicing that causes C-terminal truncation of the protein (L203 truncation) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline Myopathy.[21]
Illustrated in Fig. 3, the S108X mutation truncates ssTnT protein to cause a loss of functional structures equivalent to that of E180X. The exon 8 deletion destructs the middle region tropomyosin-binding site 1.[15][22] The L203 truncation deletes the binding sites for TnI and TnC but preserves both tropomyosin-binding sites 1 and 2.[15] It remains to be invistigated whether this novel mutation is able to bind the actin-tropomyosin thin filament in vivo and how it causes recessive nemaline myopathy.
Alternative splicing of exon 5 produces high and low molecular weight splice forms of ssTnT. The low molecular ssTnT was significantly upregulated in type 1 (demyelination) but not type 2 (axon loss) Charcot-Marie-Tooth disease,[12] suggesting that structural modification of TnT in the myofilaments may contribute to adaptation to abnormalities in neuronal activation.
# Interactions
TNNT1 has been shown to interact with PRKG1.[23]
[24]
[25]
[26]
# Notes | https://www.wikidoc.org/index.php/TNNT1 | |
d0843f88baed225eb9ee9b6f5ba733bbd5cae133 | wikidoc | TNNT2 | TNNT2
Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene. Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.
The TNNT2 gene is located at 1q32 in the human chromosomal genome, encoding the cardiac muscle isoform of troponin T (cTnT). Human cTnT is an ~36-kDa protein consisting of 297 amino acids including the first methionine with an isoelectric point (pI) of 4.88. It is the tropomyosin- binding and thin filament anchoring subunit of the troponin complex in cardiac muscle cells. TNNT2 gene is expressed in vertebrate cardiac muscles and embryonic skeletal muscles.
# Structure
Cardiac TnT is a 35.9 kDa protein composed of 298 amino acids. Cardiac TnT is the largest of the three troponin subunits (cTnT, troponin I (TnI), troponin C (TnC)) on the actin thin filament of cardiac muscle. The structure of TnT is asymmetric; the globular C-terminal domain interacts with tropomyosin (Tm), TnI and TnC, and the N-terminal tether which strongly binds Tm. The N-terminal region of TnT is alternatively spliced, accounting for multiple isoforms observed in cardiac muscle.
# Function
As part of the Troponin complex, the function of cTnT is to regulate muscle contraction. The N-terminal region of TnT that strongly binds actin most likely moves with Tm and actin during strong myosin crossbridge binding and force generation. This region is likely involved in the transduction of cooperativity down the thin filament. The C-terminal region of TnT constitutes part of the globular troponin complex domain, and participates in employing the calcium sensitivity of strong myosin crossbridge binding to the thin filament.
# Clinical significance
Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with restrictive and dilated cardiomyopathy. Transcripts for this gene undergo alternative splicing that results in many tissue-specific isoforms, however, the full-length nature of some of these variants has not yet been determined. Mutations of this gene may be associated with mild or absent hypertrophy and predominant restrictive disease, with a high risk of sudden cardiac death. Advancement to dilated cardiomyopathy may be more rapid in patients with TNNT2 mutations than in those with myosin heavy chain mutations.
# Evolution
Three homologous genes have evolved in vertebrates encoding three muscle type- specific isoforms of TnT. Each of the TnT isoform genes is linked in chromosomal DNA to a troponin I (TnI) isoform gene encoding the inhibitory subunit of the troponin complex to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, slow skeletal muscle TnI (ssTnI)-cTnT, and cTnI-ssTnT pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type-specific TnT and TnI isoforms have originated from a TnI-like ancestor gene and duplicated and diversified from a fsTnI-like-fsTnT-like gene pair.
The apparently scrambled linkage between ssTnI-cTnT and cTnI-ssTnT genes actually reflects original functional linkages as that TNNT2 gene is expressed together with ssTnI gene in embryonic cardiac muscle. Protein sequence alignment demonstrated that TNNT2 gene is conserved in vertebrate species (Fig. 2) in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged.
# Alternative splicing
Mammalian TNNT2 gene contains 14 constitutive exons and 3 alternatively spliced exons. Exons 4 and 5 encoding the N-terminal variable region and exon 13 between the middle and C-terminal regions are alternatively spliced. Exon 5 encodes a 9 or 10 amino acid segment that is highly acidic and negatively charged at physiological pH. Exon 5 is expressed in embryonic heart, down-regulated and ceases express during postnatal development.
Embryonic cTnT with more negative charge at the N-terminal region exerts higher calcium sensitivity of actomyosin ATPase activity and myofilament force production, compared with the adult cardiac TnT, as well as a higher tolerance to acidosis.
TNNT2 gene is transiently expressed in embryonic and neonatal skeletal muscles in both avian and mammalian organisms. When TNNT2 is expressed in neonatal skeletal muscle, the alternative splicing of exon 5 exhibits a synchronized regulation to that in the heart in a species-specific manner. This phenomenon indicates that alternative splicing of TNNT2 pre-mRNA is under the control of a genetically built- in systemic biological clock.
# Posttranslational modifications
## Phosphorylation
Ser2 of cTnT at the N terminus is constitutively phosphorylated by unknown mechanisms. cTnT has been found to be phosphorylated by PKC at Thr197, Ser201, Thr206, Ser208 and Thr287 in the C-terminal region. Phosphorylation of Thr206 alone was sufficient to reduce myofilament calcium sensitivity and force production. cTnT is also phosphorylated at Thr194 and Ser198 under stress conditions, leading to attenuated cardiomyocyte contractility. Phosphorylation of cTnT at Ser278 and Thr287 by ROCK-II was shown to decrease myosin ATPase activity and myofilament force development in skinned cardiac muscle. Table 1 summarizes the phosphorylation modifications of cTnT and possible functions.
## O-linked GlcNAcylation
cTnT is increasingly modified at Ser190 by O-GlcNAcylation during the development of heart failure in rat, accompanied by decreased phosphorylation of Ser208.
## Proteolytic modification
In apoptotic cardiomyocytes, cTnT was cleaved by caspase 3 to generate a 25-kDa N-terminal truncated fragment. This destructive fragmentation removes a part of the middle region tropomyosin binding site 1, leading to attenuation of the myofilament force production by decreasing the myosin ATPase activity.
In cardiac muscle under stress conditions, cardiac TnT is cleaved by calpain I, restrictively removing the entire N-terminal variable region. This proteolytic modification of cTnT occurs in cardiac muscle in acute ischemia-reperfusion or pressure overload.
The restrictively N-terminal truncated cTnT remains functional in the myofilaments and leads to reduced contractile velocity of the ventricular muscle, which extends the rapid ejection phase and results in an increase in stroke volume, especially under increased afterload. In vitro studies showed that N-terminal truncated cTnT preserved the overall cardiac myofilament calcium sensitivity and cooperativity, but altered TnT’s binding affinities for tropomyosin, TnI and TnC proteins, and lead to slightly decreased maximum myosin ATPase activity and myofilament force production, which forms the basis of the selective decrease in contractile velocity of ventricular muscle to increase stroke volume without significant increase in energy expenditure.
With the relatively short half life of cTnT in cardiomyocytes (3–4 days), the N-terminal truncated cTnT would be replaced by newly synthesized intact cTnT in several days. Therefore, this mechanism provides a reversible posttranslational regulation to modulate cardiac function in adaptation to stress conditions.
The residues in cardiac TnT with phosphorylation regulations are summarized. The residue numbers for phosphorylatable serine and threonine are that in human cardiac TnT with the first methionine included. The phosphorylation of cardiac TnT at these residues is compared with the counterparts in fast TnT and slow TnT. C, conserved; N, non-conserved. Kinases responsible for each phosphorylation, functional effects, and references are also listed.
# Mutations in cardiomyopathies
Point mutations in TNNT2 gene cause various types of cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The table below summarizes representative TNNT2 mutations and abnormal splicings found in human and animal cardiomyopathies.
Amino Acid residues of mutations were numbered as in human cardiac TnT with the first methionine included. Mutations of cardiac TnT that caused cardiomyopathies were mostly found in the conserved middle and C-terminal regions.
# Notes | TNNT2
Cardiac muscle troponin T (cTnT) is a protein that in humans is encoded by the TNNT2 gene.[1][2] Cardiac TnT is the tropomyosin-binding subunit of the troponin complex, which is located on the thin filament of striated muscles and regulates muscle contraction in response to alterations in intracellular calcium ion concentration.
The TNNT2 gene is located at 1q32 in the human chromosomal genome, encoding the cardiac muscle isoform of troponin T (cTnT). Human cTnT is an ~36-kDa protein consisting of 297 amino acids including the first methionine with an isoelectric point (pI) of 4.88. It is the tropomyosin- binding and thin filament anchoring subunit of the troponin complex in cardiac muscle cells.[3][4][5] TNNT2 gene is expressed in vertebrate cardiac muscles and embryonic skeletal muscles.[4][5][6]
# Structure
Cardiac TnT is a 35.9 kDa protein composed of 298 amino acids.[7][8] Cardiac TnT is the largest of the three troponin subunits (cTnT, troponin I (TnI), troponin C (TnC)) on the actin thin filament of cardiac muscle. The structure of TnT is asymmetric; the globular C-terminal domain interacts with tropomyosin (Tm), TnI and TnC, and the N-terminal tether which strongly binds Tm. The N-terminal region of TnT is alternatively spliced, accounting for multiple isoforms observed in cardiac muscle.[9]
# Function
As part of the Troponin complex, the function of cTnT is to regulate muscle contraction. The N-terminal region of TnT that strongly binds actin most likely moves with Tm and actin during strong myosin crossbridge binding and force generation. This region is likely involved in the transduction of cooperativity down the thin filament.[10] The C-terminal region of TnT constitutes part of the globular troponin complex domain, and participates in employing the calcium sensitivity of strong myosin crossbridge binding to the thin filament.[11]
# Clinical significance
Mutations in this gene have been associated with familial hypertrophic cardiomyopathy as well as with restrictive[12] and dilated cardiomyopathy. Transcripts for this gene undergo alternative splicing that results in many tissue-specific isoforms, however, the full-length nature of some of these variants has not yet been determined.[13] Mutations of this gene may be associated with mild or absent hypertrophy and predominant restrictive disease, with a high risk of sudden cardiac death.[12] Advancement to dilated cardiomyopathy may be more rapid in patients with TNNT2 mutations than in those with myosin heavy chain mutations.[14][15]
# Evolution
Three homologous genes have evolved in vertebrates encoding three muscle type- specific isoforms of TnT.[5] Each of the TnT isoform genes is linked in chromosomal DNA to a troponin I (TnI) isoform gene encoding the inhibitory subunit of the troponin complex to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, slow skeletal muscle TnI (ssTnI)-cTnT, and cTnI-ssTnT pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type-specific TnT and TnI isoforms have originated from a TnI-like ancestor gene and duplicated and diversified from a fsTnI-like-fsTnT-like gene pair.[16]
The apparently scrambled linkage between ssTnI-cTnT and cTnI-ssTnT genes actually reflects original functional linkages as that TNNT2 gene is expressed together with ssTnI gene in embryonic cardiac muscle.[17] Protein sequence alignment demonstrated that TNNT2 gene is conserved in vertebrate species (Fig. 2) in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged.[4][5]
# Alternative splicing
Mammalian TNNT2 gene contains 14 constitutive exons and 3 alternatively spliced exons.[18] Exons 4 and 5 encoding the N-terminal variable region and exon 13 between the middle and C-terminal regions are alternatively spliced.[19] Exon 5 encodes a 9 or 10 amino acid segment that is highly acidic and negatively charged at physiological pH.[4] Exon 5 is expressed in embryonic heart, down-regulated and ceases express during postnatal development.[20]
Embryonic cTnT with more negative charge at the N-terminal region exerts higher calcium sensitivity of actomyosin ATPase activity and myofilament force production, compared with the adult cardiac TnT, as well as a higher tolerance to acidosis.[21]
TNNT2 gene is transiently expressed in embryonic and neonatal skeletal muscles in both avian and mammalian organisms.[17][22][23] When TNNT2 is expressed in neonatal skeletal muscle, the alternative splicing of exon 5 exhibits a synchronized regulation to that in the heart in a species-specific manner.[17] This phenomenon indicates that alternative splicing of TNNT2 pre-mRNA is under the control of a genetically built- in systemic biological clock.
# Posttranslational modifications
## Phosphorylation
Ser2 of cTnT at the N terminus is constitutively phosphorylated by unknown mechanisms.[3] cTnT has been found to be phosphorylated by PKC at Thr197, Ser201, Thr206, Ser208 and Thr287 in the C-terminal region. Phosphorylation of Thr206 alone was sufficient to reduce myofilament calcium sensitivity and force production.[24][25][26][27] cTnT is also phosphorylated at Thr194 and Ser198 under stress conditions,[28] leading to attenuated cardiomyocyte contractility. Phosphorylation of cTnT at Ser278 and Thr287 by ROCK-II was shown to decrease myosin ATPase activity and myofilament force development in skinned cardiac muscle.[29] Table 1 summarizes the phosphorylation modifications of cTnT and possible functions.
## O-linked GlcNAcylation
cTnT is increasingly modified at Ser190 by O-GlcNAcylation during the development of heart failure in rat, accompanied by decreased phosphorylation of Ser208.[27]
## Proteolytic modification
In apoptotic cardiomyocytes, cTnT was cleaved by caspase 3 to generate a 25-kDa N-terminal truncated fragment.[30] This destructive fragmentation removes a part of the middle region tropomyosin binding site 1,[16] leading to attenuation of the myofilament force production by decreasing the myosin ATPase activity.[30]
In cardiac muscle under stress conditions, cardiac TnT is cleaved by calpain I, restrictively removing the entire N-terminal variable region.[31][32] This proteolytic modification of cTnT occurs in cardiac muscle in acute ischemia-reperfusion or pressure overload.[33]
The restrictively N-terminal truncated cTnT remains functional in the myofilaments and leads to reduced contractile velocity of the ventricular muscle, which extends the rapid ejection phase and results in an increase in stroke volume, especially under increased afterload.[33] In vitro studies showed that N-terminal truncated cTnT preserved the overall cardiac myofilament calcium sensitivity and cooperativity, but altered TnT’s binding affinities for tropomyosin, TnI and TnC proteins,[34][35] and lead to slightly decreased maximum myosin ATPase activity and myofilament force production, which forms the basis of the selective decrease in contractile velocity of ventricular muscle to increase stroke volume without significant increase in energy expenditure.[33]
With the relatively short half life of cTnT in cardiomyocytes (3–4 days),[36] the N-terminal truncated cTnT would be replaced by newly synthesized intact cTnT in several days. Therefore, this mechanism provides a reversible posttranslational regulation to modulate cardiac function in adaptation to stress conditions.
The residues in cardiac TnT with phosphorylation regulations are summarized. The residue numbers for phosphorylatable serine and threonine are that in human cardiac TnT with the first methionine included. The phosphorylation of cardiac TnT at these residues is compared with the counterparts in fast TnT and slow TnT. C, conserved; N, non-conserved. Kinases responsible for each phosphorylation, functional effects, and references are also listed.
# Mutations in cardiomyopathies
Point mutations in TNNT2 gene cause various types of cardiomyopathies, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM). The table below summarizes representative TNNT2 mutations and abnormal splicings found in human and animal cardiomyopathies.
Amino Acid residues of mutations were numbered as in human cardiac TnT with the first methionine included. Mutations of cardiac TnT that caused cardiomyopathies were mostly found in the conserved middle and C-terminal regions.
# Notes | https://www.wikidoc.org/index.php/TNNT2 | |
d328dbe3a5994e02220b663499eb744807f1b3c9 | wikidoc | TNNT3 | TNNT3
Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene.
The TNNT3 gene is located at 11p15.5 in the human genome, encoding the fast skeletal muscle isoform of troponin T (fsTnT). fsTnT is an ~31-kDa protein consisting of 268 amino acids including the first methionine with an isoelectric point (pI) of 6.21 (embryonic form). fsTnT is the tropomyosin-binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of fast twitch skeletal muscle. TNNT3 gene is specifically expressed in vertebrate fast twitch skeletal muscles.
# Evolution
TNNT3 gene evolved as one of the three TnT isoform genes in vertebrates. Each of the TnT isoform genes is linked to an upstream troponin I (TnI, one of the other two subunits of the troponin complex) isoform gene, and fsTnT is linked with fsTnI genes (Fig. 1). Sequence homology and protein epitope allosteric similarity data suggest that TnT gene was originated by duplication of a TnI-like ancestor gene and fsTnT was the first TnT emerged. Whereas significantly diverged from the slow skeletal muscle TnT (ssTnT encoded by TNNT1) and cardiac TnT (cTnT encoded by TNNT2), Structure of fsTnT is conserved among vertebrate species (Fig. 2), reflecting specialized functional features of the different muscle fiber types.
# Alternative splicing
Mammalian TNNT3 gene contains 19 exons. Alternative RNA splicing of 8 of them significantly increases structural variations of fsTnT. Two variable regions of the fsTnT protein are generated by alternative splicing (Fig. 3).
In the N-terminal region of fsTnT, exons 4, 5, 6, 7 and 8 are alternatively spliced in adult skeletal muscle cells. A fetal fsTnT exon located between exons 8 and 9 is specifically expressed in embryonic muscle (Briggs and Schachat 1993). Exons 16 and 17, previously designated as α and β exons, in the C-terminal region of fsTnT are alternatively spliced in a mutually exclusive manner.
Avian Tnnt3 gene has evolved with additional alternatively spliced exons, w, P1-7(x) and y, encoding the N-terminal variable region (Fig. 3). Reflecting the power of combined alternative splicing of multiple exons to generate fsTnT variants, two-dimensional gel electrophoresis detected more than 40 different fsTnT splice forms in chicken leg muscle.
# Developmental regulation
Through alternative splicing of the fetal exon and other alternative exons in the N-terminal variable region, the expression of fsTnT during mammalian and avian development undergoes a high molecular to low molecular weight isoform switch in both fast and slow fiber dominant skeletal muscles. The inclusion of more N-terminal exons increases the negative charge that tunes the overall molecular conformation of fsTnT and alters interaction with TnI, TnC and tropomyosin. The alternative splicing-based addition of N-terminal negative charge in fsTnT also contributes to the tolerance to acidosis.
Alternative splicing of the two C-terminal mutually exclusive exons 16 and 17 appears also regulated during development. Exon 17 with a sequence more similar to the counterpart segment in ssTnT and cTnT is predominantly expressed in embryonic and neonatal fsTnT. Exon 16 of fsTnT was only found in adult skeletal muscles. Exons 16 and 17 both encode a 14 amino acids peptide fragment residing in the α-helix interfacing with TnI and TnC. Protein interaction studies revealed that incorporation of exon 17 weakened binding of fsTnT to TnC and tropomyosin. Therefore, alternative splicing of exons 16 and 17 regulates the binding of fsTnT with TnI, possibly TnC, and thus tunes the function of the troponin complex and skeletal muscle contractility during development.
Avian Tnnt3 gene with additional alternatively spliced exons has unique expression pattern. The seven P exons are specifically expressed in pectoral muscles but not leg muscles. During post hatch development of the avian pectoral muscles, the segment encoded by the P exons (named Tx from the original annotation of the coding exons as an x exon) is up-regulated and included predominantly in fsTnT of adult pectoral muscles. Each P exon encodes a pentapeptide AHH(A/E)A. The Tx segment of adult fsTnT in avian orders of Galliformes and Craciformes contains 7-9 H(A/E)AAH repeats that possess high affinity binding to transition metal ions Cu(II), Ni(II), Zn(II) and Co(II). The Tx segment of chicken breast muscle fsTnT also a binding capacity for calcium, presumably serves as a calcium reservoir in avian fast pectoral muscles. Together with more N-terminal negative charges, this function may contribute to the higher calcium sensitivity of chicken breast muscle than that of leg muscle.
The switch of high to low molecular weight splice forms occurs in avian leg muscles during post hatching development similar to that in developing mammalian skeletal muscles. Early during post hatch development of chicken pectoral muscles, fsTnT also shows a high to low molecular weight switch. However, around 28 days after hatch, fsTnT with Tx segment spliced-in is rapidly up-regulated and becomes the major fsTnT splice form in adult pectoral muscles.
Deficiency of ssTnT did not affect the developmental switch of fsTnT splice forms in ssTnT-null mice, indicating that the developmental alternative splicing of the fsTnT pre-mRNA is regulated independent of skeletal muscle fiber type abnormality and adaptation.
# Notes | TNNT3
Fast skeletal muscle troponin T (fTnT) is a protein that in humans is encoded by the TNNT3 gene.[1][2]
The TNNT3 gene is located at 11p15.5 in the human genome, encoding the fast skeletal muscle isoform of troponin T (fsTnT). fsTnT is an ~31-kDa protein consisting of 268 amino acids including the first methionine with an isoelectric point (pI) of 6.21 (embryonic form). fsTnT is the tropomyosin-binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of fast twitch skeletal muscle.[3][4][5] TNNT3 gene is specifically expressed in vertebrate fast twitch skeletal muscles.[4][5][6]
# Evolution
TNNT3 gene evolved as one of the three TnT isoform genes in vertebrates. Each of the TnT isoform genes is linked to an upstream troponin I (TnI, one of the other two subunits of the troponin complex) isoform gene, and fsTnT is linked with fsTnI genes (Fig. 1). Sequence homology and protein epitope allosteric similarity data suggest that TnT gene was originated by duplication of a TnI-like ancestor gene and fsTnT was the first TnT emerged.[7] Whereas significantly diverged from the slow skeletal muscle TnT (ssTnT encoded by TNNT1) and cardiac TnT (cTnT encoded by TNNT2), Structure of fsTnT is conserved among vertebrate species (Fig. 2), reflecting specialized functional features of the different muscle fiber types.[3][4][5]
# Alternative splicing
Mammalian TNNT3 gene contains 19 exons. Alternative RNA splicing of 8 of them significantly increases structural variations of fsTnT.[8] Two variable regions of the fsTnT protein are generated by alternative splicing (Fig. 3).
In the N-terminal region of fsTnT, exons 4, 5, 6, 7 and 8 are alternatively spliced in adult skeletal muscle cells.[8][9][10] A fetal fsTnT exon located between exons 8 and 9 is specifically expressed in embryonic muscle (Briggs and Schachat 1993). Exons 16 and 17, previously designated as α and β exons, in the C-terminal region of fsTnT are alternatively spliced in a mutually exclusive manner.[11]
Avian Tnnt3 gene has evolved with additional alternatively spliced exons, w, P1-7(x) and y, encoding the N-terminal variable region (Fig. 3).[12][13][14] Reflecting the power of combined alternative splicing of multiple exons to generate fsTnT variants, two-dimensional gel electrophoresis detected more than 40 different fsTnT splice forms in chicken leg muscle.[15]
# Developmental regulation
Through alternative splicing of the fetal exon and other alternative exons in the N-terminal variable region, the expression of fsTnT during mammalian and avian development undergoes a high molecular to low molecular weight isoform switch in both fast and slow fiber dominant skeletal muscles.[16] The inclusion of more N-terminal exons increases the negative charge that tunes the overall molecular conformation of fsTnT and alters interaction with TnI, TnC and tropomyosin.[17][18][19] The alternative splicing-based addition of N-terminal negative charge in fsTnT also contributes to the tolerance to acidosis.[20]
Alternative splicing of the two C-terminal mutually exclusive exons 16 and 17 appears also regulated during development.[10] Exon 17 with a sequence more similar to the counterpart segment in ssTnT and cTnT is predominantly expressed in embryonic and neonatal fsTnT.[10][21] Exon 16 of fsTnT was only found in adult skeletal muscles. Exons 16 and 17 both encode a 14 amino acids peptide fragment residing in the α-helix interfacing with TnI and TnC. Protein interaction studies revealed that incorporation of exon 17 weakened binding of fsTnT to TnC and tropomyosin.[22] Therefore, alternative splicing of exons 16 and 17 regulates the binding of fsTnT with TnI, possibly TnC, and thus tunes the function of the troponin complex and skeletal muscle contractility during development.
Avian Tnnt3 gene with additional alternatively spliced exons has unique expression pattern. The seven P exons are specifically expressed in pectoral muscles but not leg muscles.[20] During post hatch development of the avian pectoral muscles, the segment encoded by the P exons (named Tx from the original annotation of the coding exons as an x exon) is up-regulated and included predominantly in fsTnT of adult pectoral muscles.[23] Each P exon encodes a pentapeptide AHH(A/E)A. The Tx segment of adult fsTnT in avian orders of Galliformes and Craciformes contains 7-9 H(A/E)AAH repeats that possess high affinity binding to transition metal ions Cu(II), Ni(II), Zn(II) and Co(II).[23] The Tx segment of chicken breast muscle fsTnT also a binding capacity for calcium, presumably serves as a calcium reservoir in avian fast pectoral muscles.[24] Together with more N-terminal negative charges, this function may contribute to the higher calcium sensitivity of chicken breast muscle than that of leg muscle.[25]
The switch of high to low molecular weight splice forms occurs in avian leg muscles during post hatching development similar to that in developing mammalian skeletal muscles. Early during post hatch development of chicken pectoral muscles, fsTnT also shows a high to low molecular weight switch. However, around 28 days after hatch, fsTnT with Tx segment spliced-in is rapidly up-regulated and becomes the major fsTnT splice form in adult pectoral muscles.[23]
Deficiency of ssTnT did not affect the developmental switch of fsTnT splice forms in ssTnT-null mice, indicating that the developmental alternative splicing of the fsTnT pre-mRNA is regulated independent of skeletal muscle fiber type abnormality and adaptation.[16]
# Notes | https://www.wikidoc.org/index.php/TNNT3 | |
b9130cddc52b4f73dd33e397bd3ca3af361250aa | wikidoc | TOP2A | TOP2A
DNA topoisomerase 2-alpha is an enzyme that in humans is encoded by the TOP2A gene.
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia.
# Interactions
TOP2A has been shown to interact with HDAC1, CDC5L, Small ubiquitin-related modifier 1 and P53. | TOP2A
DNA topoisomerase 2-alpha is an enzyme that in humans is encoded by the TOP2A gene.
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia.[1]
# Interactions
TOP2A has been shown to interact with HDAC1,[2][3] CDC5L,[4] Small ubiquitin-related modifier 1[5] and P53.[6] | https://www.wikidoc.org/index.php/TOP2A | |
a8bebb1f0d6341796ea692d880ed5e39c09cfccb | wikidoc | TOP3A | TOP3A
DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.
# Function
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells.
# Meiosis
Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and see Figure). The pathway leading to a NCO is referred to as Synthesis-dependent strand annealing (SDSA).
In the plant Arabidopsis thaliana, multiple mechanisms limit meiotic COs. During meiosis TOP3A and RECQ4A/B helicase antagonize formation of COs in parallel to FANCM helicase. Sequela-Arnaud et al. suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.
In the budding yeast Saccharomyces cerevisiae, the topoisomerase III (TOP3)-RMI1 heterodimer (that catalyzes DNA single-strand passage) forms a conserved complex with Sgs1 helicase (an ortholog of the human Bloom syndrome helicase). This complex promotes early formation of NCO recombinants during meiosis The TOP3-RMI1 strand passage activity appears to have two important functions during meiosis. First, strand passage activity is employed early in coordination with Sgs1 helicase to promote proper recombination pathway choice. Second, strand passage activity is used later, independently of Sgs1 helicase, to prevent the persistence of unresolvable strand entanglements in recombination intermediates.
# Interactions
TOP3A has been shown to interact with Bloom syndrome protein. | TOP3A
DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.[1][2]
# Function
This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells.[2]
# Meiosis
Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and see Figure). The pathway leading to a NCO is referred to as Synthesis-dependent strand annealing (SDSA).
In the plant Arabidopsis thaliana, multiple mechanisms limit meiotic COs.[3] During meiosis TOP3A and RECQ4A/B helicase antagonize formation of COs in parallel to FANCM helicase.[3] Sequela-Arnaud et al.[3] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.
In the budding yeast Saccharomyces cerevisiae, the topoisomerase III (TOP3)-RMI1 heterodimer (that catalyzes DNA single-strand passage) forms a conserved complex with Sgs1 helicase (an ortholog of the human Bloom syndrome helicase). This complex promotes early formation of NCO recombinants during meiosis[4] The TOP3-RMI1 strand passage activity appears to have two important functions during meiosis.[4] First, strand passage activity is employed early in coordination with Sgs1 helicase to promote proper recombination pathway choice. Second, strand passage activity is used later, independently of Sgs1 helicase, to prevent the persistence of unresolvable strand entanglements in recombination intermediates.
# Interactions
TOP3A has been shown to interact with Bloom syndrome protein.[5][6][7][8] | https://www.wikidoc.org/index.php/TOP3A | |
c7c4c5ca5baf4f4daea759c40ec1f38bff0ce05b | wikidoc | TPCN1 | TPCN1
Two pore segment channel 1 (TPC1) is a human protein encoded by the TPCN1 gene. The protein encoded by this gene is an ion channel. In contrast to other calcium and sodium channels which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domains (each containing segments S1 to S6).
# Structure
The structure of a TPC1 ortholog from Arabidopsis thaliana has been solved by two laboratories. The structures were solved using X-ray crystallography and contained the fold of a voltage-gated ion channel and EF hands. Only a single voltage sensor domain appears to responsible for voltage sensing.
# Filoviral Infections
Genetic knockout and pharmacological inhibition experiments demonstrate that Two-pore Channels, TPC1 and TPC2, are required for infection by Filoviruses Ebola and Marburg in mice. | TPCN1
Two pore segment channel 1 (TPC1) is a human protein encoded by the TPCN1 gene.[1] The protein encoded by this gene is an ion channel. In contrast to other calcium and sodium channels which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domains (each containing segments S1 to S6).[2][3][4]
# Structure
The structure of a TPC1 ortholog from Arabidopsis thaliana has been solved by two laboratories.[5][6] The structures were solved using X-ray crystallography and contained the fold of a voltage-gated ion channel and EF hands. Only a single voltage sensor domain appears to responsible for voltage sensing.
# Filoviral Infections
Genetic knockout and pharmacological inhibition experiments demonstrate that Two-pore Channels, TPC1 and TPC2, are required for infection by Filoviruses Ebola and Marburg in mice.[7] | https://www.wikidoc.org/index.php/TPCN1 | |
a03a02f42c980b54e54a00d6aa8758a80266d343 | wikidoc | TPCN2 | TPCN2
Two pore segment channel 2 (TPC2) is a human protein encoded by the TPCN2 is a protein which in humans is encoded by the TPCN2 gene. TPC2 is an ion channel, however, in contrast to other calcium and sodium channels which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domain (each containing segments S1 to S6).
# Structure
TPC2 is homologous to TPC1, the best characterized member of the TPC family. The structure of a TPC1 ortholog from Arabidopsis thaliana has been solved by two laboratories. The structures were solved using X-ray crystallography and contained the fold of a voltage-gated ion channel and EF hands.
# Filoviral Infections
Genetic knockout and pharmacological inhibition experiments demonstrate that Two-pore Channels, TPC1 and TPC2, are required for infection by Filoviruses Ebola and Marburg in mice. | TPCN2
Two pore segment channel 2 (TPC2) is a human protein encoded by the TPCN2 is a protein which in humans is encoded by the TPCN2 gene.[1] TPC2 is an ion channel, however, in contrast to other calcium and sodium channels which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domain (each containing segments S1 to S6).[2]
# Structure
TPC2 is homologous to TPC1, the best characterized member of the TPC family. The structure of a TPC1 ortholog from Arabidopsis thaliana has been solved by two laboratories.[3][4] The structures were solved using X-ray crystallography and contained the fold of a voltage-gated ion channel and EF hands.
# Filoviral Infections
Genetic knockout and pharmacological inhibition experiments demonstrate that Two-pore Channels, TPC1 and TPC2, are required for infection by Filoviruses Ebola and Marburg in mice.[5] | https://www.wikidoc.org/index.php/TPCN2 | |
4fe28e40ba8f5d9c06707db3410d95066a72db63 | wikidoc | TRAF2 | TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.
# Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms complexes with other TRAF proteins. TRAF2 is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-κB. The protein complex formed by TRAF2 and TRAF1 interacts with the IAP family members cIAP1 and cIAP2, and functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. cIAP1 can ubiquitinate and induce the degradation of this protein, and thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.
# Interactions
TRAF2 has been shown to interact with:
- ASK1,
- BCL10,
- BIRC2,
- Baculoviral IAP repeat-containing protein 3,
- CASP8AP2,
- CD134,
- CD137,
- CD27,
- CD40,
- CFLAR,
- CHUK,
- Caveolin 1,
- EDARADD,
- HIVEP3,
- IKK2,
- Low affinity nerve growth factor receptor,
- MAP3K14,
- MAP3K1
- MAP3K7IP2,
- MAP4K2,
- MAP4K5,
- RANK,
- RIPK1,
- SPHK1,
- TANK,
- TANK-binding kinase 1,
- TNFAIP3,
- TNFRSF13B,
- TNFRSF14,
- TNFRSF1A,
- TNFRSF1B,
- TNFSF14,
- TRADD,
- TRAF interacting protein,
- TRAF1, and
- UBE2N.
# Model organisms
Model organisms have been used in the study of TRAF2 function. A conditional knockout mouse line called Traf2tm1a(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 | TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.[1]
# Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from members of the TNF receptor superfamily. This protein directly interacts with TNF receptors, and forms complexes with other TRAF proteins. TRAF2 is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-κB. The protein complex formed by TRAF2 and TRAF1 interacts with the IAP family members cIAP1 and cIAP2, and functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. cIAP1 can ubiquitinate and induce the degradation of this protein, and thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.[2]
# Interactions
TRAF2 has been shown to interact with:
- ASK1,[3][4][5]
- BCL10,[6]
- BIRC2,[6][7][8][9][10][11]
- Baculoviral IAP repeat-containing protein 3,[6][8][9][10]
- CASP8AP2,[12]
- CD134,[13]
- CD137,[13][14]
- CD27,[15][16]
- CD40,[17][18][19]
- CFLAR,[20][21]
- CHUK,[22][23][24]
- Caveolin 1,[25][26]
- EDARADD,[27]
- HIVEP3,[28]
- IKK2,[22][23]
- Low affinity nerve growth factor receptor,[29]
- MAP3K14,[19][30]
- MAP3K1[31]
- MAP3K7IP2,[23][32]
- MAP4K2,[33]
- MAP4K5,[34]
- RANK,[35][36][37][38]
- RIPK1,[19][39][40][41]
- SPHK1,[42]
- TANK,[43][44][45][46]
- TANK-binding kinase 1,[43][47]
- TNFAIP3,[48]
- TNFRSF13B,[49]
- TNFRSF14,[50][51]
- TNFRSF1A,[7][40][52]
- TNFRSF1B,[1][39][43][44][50][53][54]
- TNFSF14,[55]
- TRADD,[19][39][41][43][52][56][57]
- TRAF interacting protein,[58]
- TRAF1,[39][43] and
- UBE2N.[59]
# Model organisms
Model organisms have been used in the study of TRAF2 function. A conditional knockout mouse line called Traf2tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[60] Male and female animals underwent a standardized phenotypic screen[61] to determine the effects of deletion.[62][63][64][65] Additional screens performed: - In-depth immunological phenotyping[66] | https://www.wikidoc.org/index.php/TRAF2 | |
e8aef606c7c9e4269f21c3ab98cac7c0efe76ac2 | wikidoc | TRAF4 | TRAF4
TNF receptor-associated factor 4 (TRAF4) also known as RING finger protein 83 (RNF83) is a protein that in humans is encoded by the TRAF4 gene.
TRAF4 is a member of the TNF receptor associated factor (TRAF) family, a family of scaffold proteins. TRAF proteins connect IL-1R/Toll and TNF receptors with signaling factors that lead to the activation of NF-κB and mitogen-activated protein kinases. However, TRAF4 is not known to interact with TNF receptors and its cellular functions are not well understood.
# Protein interactions
TRAF4 has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1), and negatively regulate NTR induced cell death and NF-kappa B activation. This protein has been found to bind to p47phox, a cytosolic regulatory factor included in a multi-protein complex known as NAD(P)H oxidase. This protein thus, is thought to be involved in the oxidative activation of MAPK8/JNK. Alternatively spliced transcript variants have been observed but the full-length nature of only one has been determined.
A recent report indicates that TRAF4 binds to NOD-Like Receptors NOD1 and NOD2, and specifically inhibits activation of NF-κB by the activated NOD2-RIP2 complex | TRAF4
TNF receptor-associated factor 4 (TRAF4) also known as RING finger protein 83 (RNF83) is a protein that in humans is encoded by the TRAF4 gene.[1][2][3]
TRAF4 is a member of the TNF receptor associated factor (TRAF) family, a family of scaffold proteins.[4] TRAF proteins connect IL-1R/Toll and TNF receptors with signaling factors that lead to the activation of NF-κB and mitogen-activated protein kinases. However, TRAF4 is not known to interact with TNF receptors and its cellular functions are not well understood.[5]
# Protein interactions
TRAF4 has been shown to interact with neurotrophin receptor, p75 (NTR/NTSR1),[6][7] and negatively regulate NTR induced cell death and NF-kappa B activation. This protein has been found to bind to p47phox, a cytosolic regulatory factor included in a multi-protein complex known as NAD(P)H oxidase. This protein thus, is thought to be involved in the oxidative activation of MAPK8/JNK. Alternatively spliced transcript variants have been observed but the full-length nature of only one has been determined.[3]
A recent report indicates that TRAF4 binds to NOD-Like Receptors NOD1 and NOD2, and specifically inhibits activation of NF-κB by the activated NOD2-RIP2 complex [8] | https://www.wikidoc.org/index.php/TRAF4 | |
c3c17d0eabf36ef838307259f3f11e4a30985506 | wikidoc | TRAIL | TRAIL
In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.
TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells, by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit. TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.
TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).
# Gene
In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members. The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.
The TRAIL gene lacks TATA and CAAT boxes and the promotor region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.
## The TRAIL gene as a drug target
TIC10 (which causes expression of TRAIL) was investigated in mice with various tumour types.
Small molecule ONC201 causes expression of TRAIL which kills some cancer cells.
# Structure
TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein (i.e. no leader sequence and an internal transmembrane domain). The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.
# Function
TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases. TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB.
In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation. Application of engineered ligands that have variable affinity for different death (DR4 and DR5) and decoy receptors (DCR1 and DCR2) may allow selective targeting of cancer cells by controlling activation of type1/type 2 pathways of cell death and single cell fluctuations.
# The TRAIL receptors as a drug target
In clinical trials only a small proportion of patients responded to various drugs that targeted TRAIL death receptors.
# Interactions
TRAIL has been shown to interact with TNFRSF10B. | TRAIL
In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.[1][2]
TRAIL is a cytokine that is produced and secreted by most normal tissue cells. It causes apoptosis primarily in tumor cells,[3] by binding to certain death receptors. TRAIL and its receptors have been used as the targets of several anti-cancer therapeutics since the mid-1990s, such as Mapatumumab. However, as of 2013, these have not shown significant survival benefit.[4] TRAIL has also been implicated as a pathogenic or protective factor in various pulmonary diseases, particularly pulmonary arterial hypertension.[5]
TRAIL has also been designated CD253 (cluster of differentiation 253) and TNFSF10 (tumor necrosis factor (ligand) superfamily, member 10).[3]
# Gene
In humans, the gene that encodes TRAIL is located at chromosome 3q26, which is not close to other TNF family members.[1] The genomic structure of the TRAIL gene spans approximately 20 kb and is composed of five exonic segments 222, 138, 42, 106, and 1245 nucleotides and four introns of approximately 8.2, 3.2, 2.3 and 2.3 kb.
The TRAIL gene lacks TATA and CAAT boxes and the promotor region contains putative response elements for transcription factors GATA, AP-1, C/EBP, SP-1, OCT-1, AP3, PEA3, CF-1, and ISRE.[citation needed]
## The TRAIL gene as a drug target
TIC10 (which causes expression of TRAIL) was investigated in mice with various tumour types.[4]
Small molecule ONC201 causes expression of TRAIL which kills some cancer cells.[6]
# Structure
TRAIL shows homology to other members of the tumor necrosis factor superfamily. It is composed of 281 amino acids and has characteristics of a type II transmembrane protein (i.e. no leader sequence and an internal transmembrane domain). The N-terminal cytoplasmic domain is not conserved across family members, however, the C-terminal extracellular domain is conserved and can be proteolytically cleaved from the cell surface. TRAIL forms a homotrimer that binds three receptor molecules.
# Function
TRAIL binds to the death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII). The process of apoptosis is caspase-8-dependent. Caspase-8 activates downstream effector caspases including procaspase-3, -6, and -7, leading to activation of specific kinases.[7] TRAIL also binds the receptors DcR1 and DcR2, which do not contain a cytoplasmic domain (DcR1) or contain a truncated death domain (DcR2). DcR1 functions as a TRAIL-neutralizing decoy-receptor. The cytoplasmic domain of DcR2 is functional and activates NFkappaB.
In cells expressing DcR2, TRAIL binding therefore activates NFkappaB, leading to transcription of genes known to antagonize the death signaling pathway and/or to promote inflammation. Application of engineered ligands that have variable affinity for different death (DR4 and DR5) and decoy receptors (DCR1 and DCR2) may allow selective targeting of cancer cells by controlling activation of type1/type 2 pathways of cell death and single cell fluctuations.
# The TRAIL receptors as a drug target
In clinical trials only a small proportion of patients responded to various drugs that targeted TRAIL death receptors.[8]
# Interactions
TRAIL has been shown to interact with TNFRSF10B.[9][10][11] | https://www.wikidoc.org/index.php/TRAIL | |
86453e8a5daea00913dc291b0f00285342918cda | wikidoc | TREM1 | TREM1
Triggering receptor expressed on myeloid cells 1 is a protein that in humans is encoded by the TREM1 gene.
# Function
Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors (see MIM 146790), CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1; MIM 107470). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Ig superfamily, such as TREM1, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1; MIM 604952) or inhibitory functions (e.g., KIR2DL1). In granulocyte cells, TREM1 is activated by C/EBPε independently from inflammatory response.
# Model organisms
Model organisms have been used in the study of TREM1 function. A conditional knockout mouse line called Trem1tm1(KOMP)Vlcg 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 | TREM1
Triggering receptor expressed on myeloid cells 1 is a protein that in humans is encoded by the TREM1 gene.[1][2][3]
# Function
Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors (see MIM 146790), CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1; MIM 107470). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Ig superfamily, such as TREM1, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1; MIM 604952) or inhibitory functions (e.g., KIR2DL1).[3] In granulocyte cells, TREM1 is activated by C/EBPε independently from inflammatory response.[4]
# Model organisms
Model organisms have been used in the study of TREM1 function. A conditional knockout mouse line called Trem1tm1(KOMP)Vlcg 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/TREM1 | |
0df37b4c6e2855ad158435f16a7c073e1b87062d | wikidoc | TREM2 | TREM2
Triggering receptor expressed on myeloid cells 2 also known as TREM-2 is a protein that in humans is encoded by the TREM2 gene.
# Function
Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Immunoglobulin (Ig) superfamily, such as TREM2, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1) or inhibitory functions (e.g., KIR2DL1).
# Clinical significance
Homozygous mutations in TREM2 are known to cause rare, autosomal recessive forms of dementia with an early onset and presenting with or without bone cysts and fractures.
A rare missense mutation (rs75932628-T) in the gene encoding TREM2, (predicted to result in an R47H substitution), confers a significant risk of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, it is suspected of interfering with the brain’s ability to prevent the buildup of plaque. TREM2 mutations increase the risk of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. TREM2 interacts with DAP12 in microglia to trigger phagocytosis of amyloid beta peptide and apoptotic neurons without inflammation. Mutations in TREM2 impair the normal proteolytic maturation of the protein which in turn interferes with phagocytosis and may therefore contribute to the pathogenesis of Alzheimer's disease.
Soluble TREM2 has been detected in human cerebrospinal fluid (CSF), where it was found to be elevated in CSF of patients with multiple sclerosis and other inflammatory neurological conditions in comparison to patients without inflammatory neurologic disorders. | TREM2
Triggering receptor expressed on myeloid cells 2 also known as TREM-2 is a protein that in humans is encoded by the TREM2 gene.[1][2][3]
# Function
Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Immunoglobulin (Ig) superfamily, such as TREM2, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1) or inhibitory functions (e.g., KIR2DL1).[3]
# Clinical significance
Homozygous mutations in TREM2 are known to cause rare, autosomal recessive forms of dementia with an early onset and presenting with[2] or without[4] bone cysts and fractures.
A rare missense mutation (rs75932628-T) in the gene encoding TREM2, (predicted to result in an R47H substitution), confers a significant risk of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, it is suspected of interfering with the brain’s ability to prevent the buildup of plaque.[5][6] TREM2 mutations increase the risk of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. TREM2 interacts with DAP12 in microglia to trigger phagocytosis of amyloid beta peptide and apoptotic neurons without inflammation. Mutations in TREM2 impair the normal proteolytic maturation of the protein which in turn interferes with phagocytosis and may therefore contribute to the pathogenesis of Alzheimer's disease.[7]
Soluble TREM2 has been detected in human cerebrospinal fluid (CSF), where it was found to be elevated in CSF of patients with multiple sclerosis and other inflammatory neurological conditions in comparison to patients without inflammatory neurologic disorders.[8] | https://www.wikidoc.org/index.php/TREM2 | |
00a54779d75ab334878c8968e883ac67ab516d28 | wikidoc | TREX1 | TREX1
Three prime repair exonuclease 1 is an enzyme that in humans is encoded by the TREX1 gene.
# Function
This gene encodes the major 3'->5' DNA exonuclease in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.
# Clinical relevance
TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm | TREX1
Three prime repair exonuclease 1 is an enzyme that in humans is encoded by the TREX1 gene.[1][2][3][4]
# Function
This gene encodes the major 3'->5' DNA exonuclease in human cells. The protein is a non-processive exonuclease that may serve a proofreading function for a human DNA polymerase. It is also a component of the SET complex, and acts to rapidly degrade 3' ends of nicked DNA during granzyme A-mediated cell death. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy), and Cree encephalitis. Multiple transcript variants encoding different isoforms have been found for this gene.[4]
# Clinical relevance
TREX1 helps HIV‑1 to evade cytosolic sensing by degrading viral cDNA in the cytoplasm[5] | https://www.wikidoc.org/index.php/TREX1 | |
8bea5654c75f67f15b1036627d2320e9a5091db0 | wikidoc | TRIB1 | TRIB1
Tribbles homolog 1 is a protein kinase that in humans is encoded by the TRIB1 gene. Orthologs of this protein pseudokinase (pseudoenzyme) can be found almost ubiquitously throughout the animal kingdom. It exerts its biological functions through binding to signalling proteins of the MAPKK level of the MAPK pathway, therefore eliciting a regulatory role in the function of this pathway which mediates proliferation, apoptosis and differentiation in cells. Tribbles-1 is encoded by the trib1 gene, which in humans can be found on chromosome 8 at position 24.13 on the longest arm (q). Recent crystal structures show that Tribbles 1 has an unusual 3D structure, containing a 'broken' C-helix region, a binding site for ubiquitinated substrates such as C/EBPalpha and a key regulatory C-tail region. Like TRIB2 and TRIB3, TRIB1 has recently been considered as a potential allosteric drug target
# Function
Tribbles-1 is one of three members of the Tribbles subfamily, which is a part of the CAMK Ser/Thr protein kinase family, of the protein kinase superfamily. The Tribbles subfamily is one of the pseudokinases, meaning that while expressing putative kinase regions in its structure, it is non-catalytic. The Tribbles subfamily lacks a functional ATP binding pocket, and therefore cannot phosphorylate its substrates; instead, Tribbles proteins function as scaffold proteins, which bind their substrates to localize them to or from their function
Expression of Tribbles-1 is highly variable, constantly changing with respect to time and cell-type, which suggests a large amount of regulation that exists in the cell. The protein's primary structure contains a PEST region, indicative of proteins that are highly susceptible to degradation in the cell; Tribbles-1 plays a role in regulating its own expression by binding to its substrate, which not only produces its function on the MAPK pathway, but also works to protect it from degradation whilst binding. This, in part, creates a positive feedback loop in the function of Tribbles-1, as the function of Tribbles-1 directly aids in the increase of the amount of it. As positive feedback loops are often seen throughout biology in circumstances that require the alleviation of an external stimulus, the positive feedback loop exhibited by Tribbles-1 suggests that it plays a functional role in cell response.
# Clinical significance
Tribbles-1 is an inflammatory regulator.
Tribbles-1 is associated with Acute Myeloid Leukemia (AML).
Tribbles-1 has been implicated in atherosclerosis. | TRIB1
Tribbles homolog 1 is a protein kinase that in humans is encoded by the TRIB1 gene.[1][2][3] Orthologs of this protein pseudokinase (pseudoenzyme) can be found almost ubiquitously throughout the animal kingdom.[4] It exerts its biological functions through binding to signalling proteins of the MAPKK level of the MAPK pathway, therefore eliciting a regulatory role in the function of this pathway which mediates proliferation, apoptosis and differentiation in cells. Tribbles-1 is encoded by the trib1 gene, which in humans can be found on chromosome 8 at position 24.13 on the longest arm (q). Recent crystal structures show that Tribbles 1 has an unusual 3D structure, containing a 'broken' C-helix region, a binding site for ubiquitinated substrates such as C/EBPalpha and a key regulatory C-tail region.[5] Like TRIB2 and TRIB3, TRIB1 has recently been considered as a potential allosteric drug target [6]
# Function
Tribbles-1 is one of three members of the Tribbles subfamily, which is a part of the CAMK Ser/Thr protein kinase family, of the protein kinase superfamily. The Tribbles subfamily is one of the pseudokinases, meaning that while expressing putative kinase regions in its structure, it is non-catalytic. The Tribbles subfamily lacks a functional ATP binding pocket, and therefore cannot phosphorylate its substrates; instead, Tribbles proteins function as scaffold proteins, which bind their substrates to localize them to or from their function [4]
Expression of Tribbles-1 is highly variable, constantly changing with respect to time and cell-type,[7] which suggests a large amount of regulation that exists in the cell. The protein's primary structure contains a PEST region, indicative of proteins that are highly susceptible to degradation in the cell; Tribbles-1 plays a role in regulating its own expression by binding to its substrate, which not only produces its function on the MAPK pathway, but also works to protect it from degradation whilst binding. This, in part, creates a positive feedback loop in the function of Tribbles-1, as the function of Tribbles-1 directly aids in the increase of the amount of it. As positive feedback loops are often seen throughout biology in circumstances that require the alleviation of an external stimulus, the positive feedback loop exhibited by Tribbles-1 suggests that it plays a functional role in cell response.
# Clinical significance
Tribbles-1 is an inflammatory regulator.
Tribbles-1 is associated with Acute Myeloid Leukemia (AML).
Tribbles-1 has been implicated in atherosclerosis. | https://www.wikidoc.org/index.php/TRIB1 | |
49f1433b90effecc9ec5a6f1eaf8650707169cea | wikidoc | TRIP6 | TRIP6
Thyroid receptor-interacting protein 6 is a protein that in humans is encoded by the TRIP6 gene.
# Function
This gene is a member of the zyxin family and encodes a protein with three LIM zinc-binding domains. This protein localizes to focal adhesion sites and along actin stress fibers. Recruitment of this protein to the plasma membrane occurs in a lysophosphatidic acid (LPA)-dependent manner and it regulates LPA-induced cell migration. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.
# Interactions
TRIP6 has been shown to interact with LPAR2, BCAR1 and HOXA9. | TRIP6
Thyroid receptor-interacting protein 6 is a protein that in humans is encoded by the TRIP6 gene.[1][2][3]
# Function
This gene is a member of the zyxin family and encodes a protein with three LIM zinc-binding domains. This protein localizes to focal adhesion sites and along actin stress fibers. Recruitment of this protein to the plasma membrane occurs in a lysophosphatidic acid (LPA)-dependent manner and it regulates LPA-induced cell migration. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized.[3]
# Interactions
TRIP6 has been shown to interact with LPAR2,[4] BCAR1[4][5] and HOXA9.[6] | https://www.wikidoc.org/index.php/TRIP6 | |
83ac72a0688c445c154a0a3199ab548df52db666 | wikidoc | TRPA1 | TRPA1
Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1 or TRPA1, is a protein that in humans is encoded by the TRPA1 (and in other species by the Trpa1) gene.
TRPA1 is an ion channel located on the plasma membrane of many human and animal cells. This ion channel is best known as a sensor for environmental irritants giving rise to somatosensory modalities such as pain, cold and itch.
# Function
TRPA1 is a member of the transient receptor potential channel family. TRPA1 contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical and chemical stress sensor. The specific function of this protein has not yet been determined; however, studies indicate that the function may involve a role in signal transduction and growth control.
Recent studies indicate that TRPA1 is activated by a number of reactive (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases) and non-reactive compounds (nicotine, PF-4840154) and considered as a "chemosensor" in the body.. TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans. This sub-population of peripheral C-fibers is considered important sensors of nociception in humans and their activation will under normal conditions give rise to pain. Indeed, TRPA1 is considered as an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of formalin-induced pain behaviors. TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).
Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.
In the heat-sensitive loreal pit organs of many snakes TRPA1 is responsible for the detection of infrared radiation.
# Clinical significance
In 2008, it was observed that caffeine suppresses activity of human TRPA1, but it was found that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting that the TRPA1 channels mediate the perception of caffeine.
TRPA1 has also been implicated in causing the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches.
A missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from Colombia suffers from "debilitating upper-body pain starting in infancy" that is "usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors)". A gain-of-function mutation in the fourth transmembrane domain causes the channel to be overly sensitive to pharmacological activation.
Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors (probably agonism which then can lead to desensitization of TRPA1 receptors in the way that capsaicin does it in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.
Oxalate, a metabolite of an anti cancer drug oxaliplatin, has been demonstrated to inhibit prolyl hydroxylase, which endows cold-insensitive human TRPA1 with pseudo cold sensitivity (via reactive oxygen generation from mitochondria). This may cause a characteristic side-effect of oxaliplatin (cold-triggered acute peripheral neuropathy).
# Ligand binding
TRPA1 can be considered to be one of the most promiscuous TRP ion channels, as it seems to be activated by a large number of noxious chemicals found in many plants, food, cosmetics and pollutants.
Activation of the TRPA1 ion channel by the olive oil phenolic compound oleocanthal appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by olive oil.
Although several nonelectrophilic agents such as thymol and menthol have been reported as TRPA1 agonists, most of the known activators are electrophilic chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible covalent bond with cysteine residues present in the ion channel. For a broad range of electrophilic agents, chemical reactivity in combination with a lipophilicity enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenzoxazepine derivative substituted by a carboxylic methylester at position 10 is the most potent TRPA1 agonist discovered to date (EC50 = 50 pM). The pyrimidine PF-4840154 is a potent, non-covalent activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TrpA1 channels. This compound elicits nociception in a mouse model through TrpA1 activation. Furthermore, PF-4840154 is superior to allyl isothiocyanate, the pungent component of mustard oil, for screening purposes.
The eicosanoids formed in the ALOX12 (i.e. arachidonate-12-lipoxygnease) pathway of arachidonic acid metabolism, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-HpETE; see 12-Hydroxyeicosatetraenoic acid) and the hepoxilins (Hx), HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) (see Hepoxilin#Pain perception) directly activate TRPA1 and thereby contribute to the hyperalgesia and tactile allodynia responses of mice to skin inflammation. In this animal model of pain perception, the hepoxilins are released in spinal cord and directly activate TRPA (and also TRPV1) receptors to augment the perception of pain. 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins. The epoxide, 4,5-epoxy-8Z,11Z,14Z-eicosatrienoic acid (4,5-EET) made by the metabolism of arachidonic acid by any one of several cytochrome P450 enzymes (see Epoxyeicosatrienoic acid) likewise directly activates TRPA1 to amplify pain perception.
Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action does not appear to involve direct binding to TRPA1 but rather the indirect activation and/or sensitization of TRPA1 as well as TRPV1 receptors. Genetic polymorphism in the EP3 receptor (rs11209716), has been associated with ACE inhibitor-induce cough in humans.
# TRPA1 inhibition
Resolvin D1 (RvD1) and RvD2 (see resolvins) and maresin 1 are metabolites of the omega 3 fatty acid, docosahexaenoic acid. They are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, in humans. These SPMs also damp pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effect involves the inhibition of TRPA1, probably (in at least certain cases) by an indirect effect wherein they activate another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which SPMs may operate to down-regulate TRPs and thereby pain perception.
# Ligand examples
## Agonists
- 4-Oxo-2-nonenal
- Allicin
- Allyl isothiocyanate
- Cannabidiol
- Gingerol
- Icilin
- Polygodial
- Hepoxilins A3 and B3
- 12S-Hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid
- 4,5-Epoxyeicosatrienoic acid
- CBC
- Supercinnamaldehyde
## Antagonists
- HC030031
- GRC17536
- A-967079
- ALGX-2513
- ALGX-2541
- ALGX-2563
- ALGX-2561
- ALGX-2542 | TRPA1
Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1 or TRPA1, is a protein that in humans is encoded by the TRPA1 (and in other species by the Trpa1) gene.[1][2]
TRPA1 is an ion channel located on the plasma membrane of many human and animal cells. This ion channel is best known as a sensor for environmental irritants giving rise to somatosensory modalities such as pain, cold and itch.[3][4]
# Function
TRPA1 is a member of the transient receptor potential channel family.[2] TRPA1 contains 14 N-terminal ankyrin repeats and is believed to function as a mechanical and chemical stress sensor.[5] The specific function of this protein has not yet been determined; however, studies indicate that the function may involve a role in signal transduction and growth control.[6]
Recent studies indicate that TRPA1 is activated by a number of reactive [3][4][7] (allyl isothiocyanate, cinnamaldehyde, farnesyl thiosalicylic acid, formalin, hydrogen peroxide, 4-hydroxynonenal, acrolein, and tear gases[8]) and non-reactive compounds (nicotine,[9] PF-4840154[10]) and considered as a "chemosensor" in the body.[11]. TRPA1 is co-expressed with TRPV1 on nociceptive primary afferent C-fibers in humans.[12] This sub-population of peripheral C-fibers is considered important sensors of nociception in humans and their activation will under normal conditions give rise to pain.[13] Indeed, TRPA1 is considered as an attractive pain target based on the fact that TRPA1 knockout mice showed near complete attenuation of formalin-induced pain behaviors.[14][15] TRPA1 antagonists are effective in blocking pain behaviors induced by inflammation (complete Freund's adjuvant and formalin).
Although it is not firmly confirmed whether noxious cold sensation is mediated by TRPA1 in vivo, several recent studies clearly demonstrated cold activation of TRPA1 channels in vitro.[16][17]
In the heat-sensitive loreal pit organs of many snakes TRPA1 is responsible for the detection of infrared radiation.[18]
# Clinical significance
In 2008, it was observed that caffeine suppresses activity of human TRPA1, but it was found that mouse TRPA1 channels expressed in sensory neurons cause an aversion to drinking caffeine-containing water, suggesting that the TRPA1 channels mediate the perception of caffeine.[19]
TRPA1 has also been implicated in causing the skin irritation experienced by some smokers trying to quit by using nicotine replacement therapies such as inhalers, sprays, or patches.[9]
A missense mutation of TRPA1 was found to be the cause of a hereditary episodic pain syndrome. A family from Colombia suffers from "debilitating upper-body pain starting in infancy" that is "usually triggered by fasting or fatigue (illness, cold temperature, and physical exertion being contributory factors)". A gain-of-function mutation in the fourth transmembrane domain causes the channel to be overly sensitive to pharmacological activation.[20]
Metabolites of paracetamol (acetaminophen) have been demonstrated to bind to the TRPA1 receptors (probably agonism which then can lead to desensitization of TRPA1 receptors in the way that capsaicin does it in the spinal cord of mice, causing an antinociceptive effect. This is suggested as the antinociceptive mechanism for paracetamol.[21]
Oxalate, a metabolite of an anti cancer drug oxaliplatin, has been demonstrated to inhibit prolyl hydroxylase, which endows cold-insensitive human TRPA1 with pseudo cold sensitivity (via reactive oxygen generation from mitochondria). This may cause a characteristic side-effect of oxaliplatin (cold-triggered acute peripheral neuropathy).[22]
# Ligand binding
TRPA1 can be considered to be one of the most promiscuous TRP ion channels, as it seems to be activated by a large number of noxious chemicals found in many plants, food, cosmetics and pollutants.[23]
Activation of the TRPA1 ion channel by the olive oil phenolic compound oleocanthal appears to be responsible for the pungent or "peppery" sensation in the back of the throat caused by olive oil.[24][25]
Although several nonelectrophilic agents such as thymol and menthol have been reported as TRPA1 agonists, most of the known activators are electrophilic chemicals that have been shown to activate the TRPA1 receptor via the formation of a reversible covalent bond with cysteine residues present in the ion channel.[26][27] For a broad range of electrophilic agents, chemical reactivity in combination with a lipophilicity enabling membrane permeation is crucial to TRPA1 agonistic effect. A dibenz[b,f][1,4]oxazepine derivative substituted by a carboxylic methylester at position 10 is the most potent TRPA1 agonist discovered to date (EC50 = 50 pM).[28] The pyrimidine PF-4840154 is a potent, non-covalent activator of both the human (EC50 = 23 nM) and rat (EC50 = 97 nM) TrpA1 channels. This compound elicits nociception in a mouse model through TrpA1 activation. Furthermore, PF-4840154 is superior to allyl isothiocyanate, the pungent component of mustard oil, for screening purposes.[10]
The eicosanoids formed in the ALOX12 (i.e. arachidonate-12-lipoxygnease) pathway of arachidonic acid metabolism, 12S-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (i.e. 12S-HpETE; see 12-Hydroxyeicosatetraenoic acid) and the hepoxilins (Hx), HxA3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) (see Hepoxilin#Pain perception) directly activate TRPA1 and thereby contribute to the hyperalgesia and tactile allodynia responses of mice to skin inflammation. In this animal model of pain perception, the hepoxilins are released in spinal cord and directly activate TRPA (and also TRPV1) receptors to augment the perception of pain.[29][30][31][32] 12S-HpETE, which is the direct precursor to HxA3 and HxB3 in the ALOX12 pathway, may act only after being converted to these hepoxilins.[31] The epoxide, 4,5-epoxy-8Z,11Z,14Z-eicosatrienoic acid (4,5-EET) made by the metabolism of arachidonic acid by any one of several cytochrome P450 enzymes (see Epoxyeicosatrienoic acid) likewise directly activates TRPA1 to amplify pain perception.[31]
Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action does not appear to involve direct binding to TRPA1 but rather the indirect activation and/or sensitization of TRPA1 as well as TRPV1 receptors. Genetic polymorphism in the EP3 receptor (rs11209716[33]), has been associated with ACE inhibitor-induce cough in humans.[34][35]
# TRPA1 inhibition
Resolvin D1 (RvD1) and RvD2 (see resolvins) and maresin 1 are metabolites of the omega 3 fatty acid, docosahexaenoic acid. They are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, in humans. These SPMs also damp pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effect involves the inhibition of TRPA1, probably (in at least certain cases) by an indirect effect wherein they activate another receptor located on neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which SPMs may operate to down-regulate TRPs and thereby pain perception.[36][37][38][39][40]
# Ligand examples
## Agonists
- 4-Oxo-2-nonenal
- Allicin
- Allyl isothiocyanate
- Cannabidiol
- Gingerol
- Icilin
- Polygodial
- Hepoxilins A3 and B3
- 12S-Hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid
- 4,5-Epoxyeicosatrienoic acid
- CBC
- Supercinnamaldehyde[41]
## Antagonists
- HC030031
- GRC17536
- A-967079
- ALGX-2513
- ALGX-2541
- ALGX-2563
- ALGX-2561
- ALGX-2542 | https://www.wikidoc.org/index.php/TRPA1 | |
fe3ba127f2c71f1bffb9b9d0281f41c7d318f251 | wikidoc | TRPC1 | TRPC1
Transient receptor potential channel 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.
# Function
TRPC1 is an ion channel located on the plasma membrane of numerous human and animal cell types.
It is a nonspecific cation channel, which means that both sodium and calcium ions can pass through it. TRPC1 is thought to mediate calcium entry in response to depletion of endoplasmic calcium stores or activation of receptors coupled to the phospholipase C system. In HEK293 cells the unitary current-voltage relationship of endogenous TRPC1 channels is almost linear, with a slope conductance of about 17 pS. The extrapolated reversal potential of TRPC1 channels is +30 mV.
The TRPC1 protein is widely expressed throughout the mammalian brain and has a similar corticolimbic expression pattern as TRPC4 and TRPC5.
The highest density of TRPC1 protein is found in the lateral septum, an area with dense TRPC4 expression, and hippocampus and prefrontal cortex, areas with dense TRPC5 expression.
# History
TRPC1 was the first mammalian Transient Receptor Potential channel to be identified. In 1995 it was cloned when the research groups headed by Craig Montell and Lutz Birnbaumer were searching for proteins similar to the TRP channel in Drosophila. Together with TRPC3 they became the founding members of the TRPC ion channel family.
# Interactions
TRPC1 has been shown to interact with:
- HOMER3,
- Polycystic kidney disease 2,
- RHOA
- TRPC3,
- TRPC4, and
- TRPC5. | TRPC1
Transient receptor potential channel 1 (TRPC1) is a protein that in humans is encoded by the TRPC1 gene.[1][2]
# Function
TRPC1 is an ion channel located on the plasma membrane of numerous human and animal cell types.
[3]
It is a nonspecific cation channel, which means that both sodium and calcium ions can pass through it. TRPC1 is thought to mediate calcium entry in response to depletion of endoplasmic calcium stores or activation of receptors coupled to the phospholipase C system. In HEK293 cells the unitary current-voltage relationship of endogenous TRPC1 channels is almost linear, with a slope conductance of about 17 pS. The extrapolated reversal potential of TRPC1 channels is +30 mV.[4]
The TRPC1 protein is widely expressed throughout the mammalian brain and has a similar corticolimbic expression pattern as TRPC4 and TRPC5.
[5][6] The highest density of TRPC1 protein is found in the lateral septum, an area with dense TRPC4 expression, and hippocampus and prefrontal cortex, areas with dense TRPC5 expression.[6]
# History
TRPC1 was the first mammalian Transient Receptor Potential channel to be identified. In 1995 it was cloned when the research groups headed by Craig Montell and Lutz Birnbaumer were searching for proteins similar to the TRP channel in Drosophila. Together with TRPC3 they became the founding members of the TRPC ion channel family.[1][2]
# Interactions
TRPC1 has been shown to interact with:
- HOMER3,[7]
- Polycystic kidney disease 2,[8]
- RHOA[9]
- TRPC3,[10][11]
- TRPC4,[10][12] and
- TRPC5.[10][12] | https://www.wikidoc.org/index.php/TRPC1 | |
aeafdbc371fad4d91de190a122db0a2bded9b91f | wikidoc | TRPC3 | TRPC3
Short transient receptor potential channel 3 (TrpC3) also known as transient receptor protein 3 (TRP-3) is a protein that in humans is encoded by the TRPC3 gene. The TRPC3/6/7 subfamily are implicated in the regulation of vascular tone, cell growth, proliferation and pathological hypertrophy. These are diacylgylcerol-sensitive cation channels known regulate intracellular calcium via activation of the phospholipase C (PLC) pathway and/or by sensing Ca2+ store depletion. Together, their role in calcium homeostasis has made them potential therapeutic targets for a variety of central and peripheral pathologies.
# Function
Non-specific cation conductance elicited by the activation of TrkB by BDNF is TRPC3-dependent in the CNS. TRPC channels are almost always co-localized with mGluR1-expressing cells and likely play a role in mGluR-mediated EPSPs.
The TRPC3 channel has been shown to be preferentially expressed in non-excitable cell types, such as oligodendrocytes. However, evidence suggests that active TRPC3 channels in basal ganglia (BG) output neurons are responsible for maintaining a tonic inward depolarizing current that regulates resting membrane potential and promotes regular neuronal firing. Conversely, inhibiting TRPC3 promotes cellular hyperpolarization, which can lead to slower and more irregular neuronal firing. While it's unclear if TRPC3 channels have equal expression, other members of the TRPC family have been localized to the axon hillock, cell body, and dendritic processes of dopamine-expressing cells.
The neuromodulator, substance P, activates TRPC3/7 channels inducing cellular currents that underlie rhythmic pacemaker activity in the brainstem, enhancing the regularity and frequency of respiratory rhythms, showing homology to the mechanism described in BG neurons. Transgenic cardiomyocytes expressing TRPC3 show prolonged action potential duration when exposed to a TRPC3 agonist. The same cardiomyocytes also increase their firing rate with agonist exposure under a current-clamp tetanus protocol suggesting that they may play a role in cardiac arrhythmogenesis.
# Modulators
A small molecule agonist is GSK1702934A and antagonists are GSK417651A and GSK2293017A. A commercially available inhibitor is available in the form of a pyrazole compound, Pyr3 TRPC3 has been shown to specifically interact with TRPC1 and TRPC6. | TRPC3
Short transient receptor potential channel 3 (TrpC3) also known as transient receptor protein 3 (TRP-3) is a protein that in humans is encoded by the TRPC3 gene. The TRPC3/6/7 subfamily are implicated in the regulation of vascular tone, cell growth, proliferation and pathological hypertrophy.[1] These are diacylgylcerol-sensitive cation channels known regulate intracellular calcium via activation of the phospholipase C (PLC) pathway and/or by sensing Ca2+ store depletion.[2] Together, their role in calcium homeostasis has made them potential therapeutic targets for a variety of central and peripheral pathologies.[3]
# Function
Non-specific cation conductance elicited by the activation of TrkB by BDNF is TRPC3-dependent in the CNS.[4] TRPC channels are almost always co-localized with mGluR1-expressing cells and likely play a role in mGluR-mediated EPSPs.[5]
The TRPC3 channel has been shown to be preferentially expressed in non-excitable cell types, such as oligodendrocytes.[2] However, evidence suggests that active TRPC3 channels in basal ganglia (BG) output neurons are responsible for maintaining a tonic inward depolarizing current that regulates resting membrane potential and promotes regular neuronal firing.[6] Conversely, inhibiting TRPC3 promotes cellular hyperpolarization, which can lead to slower and more irregular neuronal firing. While it's unclear if TRPC3 channels have equal expression, other members of the TRPC family have been localized to the axon hillock, cell body, and dendritic processes of dopamine-expressing cells.[7]
The neuromodulator, substance P, activates TRPC3/7 channels inducing cellular currents that underlie rhythmic pacemaker activity in the brainstem, enhancing the regularity and frequency of respiratory rhythms,[8] showing homology to the mechanism described in BG neurons. Transgenic cardiomyocytes expressing TRPC3 show prolonged action potential duration when exposed to a TRPC3 agonist.[9] The same cardiomyocytes also increase their firing rate with agonist exposure under a current-clamp tetanus protocol suggesting that they may play a role in cardiac arrhythmogenesis.
# Modulators
A small molecule agonist is GSK1702934A and antagonists are GSK417651A and GSK2293017A.[1] A commercially available inhibitor is available in the form of a pyrazole compound, Pyr3[10] TRPC3 has been shown to specifically interact with TRPC1[11][12] and TRPC6.[13] | https://www.wikidoc.org/index.php/TRPC3 | |
d2bcf1cae298fa94b19a637e8f64dcbeb6dcdd89 | wikidoc | TRPC4 | TRPC4
The short transient receptor potential channel 4 (TrpC4), also known as Trp-related protein 4, is a protein that in humans is encoded by the TRPC4 gene.
# Function
TrpC4 is a member of the transient receptor potential cation channels. This protein forms a non-selective calcium-permeable cation channel that is activated by Gαi-coupled receptors, Gαq-coupled receptors and tyrosine kinases, and plays a role in multiple processes including endothelial permeability, vasodilation, neurotransmitter release and cell proliferation.
# Tissue distribution
The nonselective cation channel TrpC4 has been shown to be present in high abundance in the cortico-limbic regions of the brain. In addition, TRPC4 mRNA is present in midbrain dopaminergic neurons in the ventral tegmental area and the substantia nigra.
# Roles
Deletion of the trpc4 gene decreases levels of sociability in a social exploration task. These results suggest that TRPC4 may play a role in regulating social anxiety in a number of different disorders. However deletion of the trpc4 gene had no impact on basic or complex strategic learning. Given that the trpc4 gene is expressed in a select population of midbrain dopamine neurons it has been proposed that is may have an important role in dopamine related processes including addiction and attention.
# Clinical significance
Single nucleotide polymorphisms in this gene may be associated with generalized epilepsy with photosensitivity.
# Interactions
TRPC4 has been shown to interact with ITPR1, TRPC1, and TRPC5. | TRPC4
The short transient receptor potential channel 4 (TrpC4), also known as Trp-related protein 4, is a protein that in humans is encoded by the TRPC4 gene.[1][2]
# Function
TrpC4 is a member of the transient receptor potential cation channels. This protein forms a non-selective calcium-permeable cation channel that is activated by Gαi-coupled receptors, Gαq-coupled receptors and tyrosine kinases, and plays a role in multiple processes including endothelial permeability, vasodilation, neurotransmitter release and cell proliferation.[3]
# Tissue distribution
The nonselective cation channel TrpC4 has been shown to be present in high abundance in the cortico-limbic regions of the brain.[4] In addition, TRPC4 mRNA is present in midbrain dopaminergic neurons in the ventral tegmental area and the substantia nigra.[5]
# Roles
Deletion of the trpc4 gene decreases levels of sociability in a social exploration task. These results suggest that TRPC4 may play a role in regulating social anxiety in a number of different disorders.[6] However deletion of the trpc4 gene had no impact on basic or complex strategic learning.[7] Given that the trpc4 gene is expressed in a select population of midbrain dopamine neurons it has been proposed that is may have an important role in dopamine related processes including addiction and attention.[5]
# Clinical significance
Single nucleotide polymorphisms in this gene may be associated with generalized epilepsy with photosensitivity.[8]
# Interactions
TRPC4 has been shown to interact with ITPR1,[9][10] TRPC1,[11][12] and TRPC5.[12] | https://www.wikidoc.org/index.php/TRPC4 | |
53d7f122f24e0b217173e2267cbf8db2951b4174 | wikidoc | TRPC5 | TRPC5
Short transient receptor potential channel 5 (TrpC5) also known as transient receptor protein 5 (TRP-5) is a protein that in humans is encoded by the TRPC5 gene. TrpC5 is subtype of the TRPC family of mammalian transient receptor potential ion channels.
# Function
TrpC5 is one of the seven mammalian TRPC (transient receptor potential canonical) proteins. TrpC5 is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na+–H+ exchange regulatory factor (NHERF), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).
TRPC4 and TRPC5 have been implicated in the mechanism of mercury toxicity and neurological behavior.
# Activation
Homomultimeric TRPC5 and heteromultimeric TRPC5-TRPC1 channels are activated by extracellular reduced thioredoxin. This channel has also been found to be involved in the action of anaesthetics such as chloroform, halothane and propofol.
# Interactions
TRPC5 has been shown to interact with STMN3, TRPC1, and TRPC4. | TRPC5
Short transient receptor potential channel 5 (TrpC5) also known as transient receptor protein 5 (TRP-5) is a protein that in humans is encoded by the TRPC5 gene.[1][2][3] TrpC5 is subtype of the TRPC family of mammalian transient receptor potential ion channels.
# Function
TrpC5 is one of the seven mammalian TRPC (transient receptor potential canonical) proteins. TrpC5 is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na+–H+ exchange regulatory factor (NHERF), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).[1]
TRPC4 and TRPC5 have been implicated in the mechanism of mercury toxicity[4] and neurological behavior.[5]
# Activation
Homomultimeric TRPC5 and heteromultimeric TRPC5-TRPC1 channels are activated by extracellular reduced thioredoxin.[6] This channel has also been found to be involved in the action of anaesthetics such as chloroform, halothane and propofol.[7]
# Interactions
TRPC5 has been shown to interact with STMN3,[8] TRPC1,[9][10] and TRPC4.[10] | https://www.wikidoc.org/index.php/TRPC5 | |
572de24cb613d340ddc7738979ddb145af5b1a69 | wikidoc | TRPM1 | TRPM1
Transient receptor potential cation channel subfamily M member 1 is a protein that in humans is encoded by the TRPM1 gene.
# Function
The protein encoded by this gene is a member of the transient receptor potential (TRP) family of non-selective cation channels. It is expressed in the retina, in a subset of bipolar cells termed ON bipolar cells. These cells form synapses with either rods or cones, collecting signals from them. In the dark, the signal arrives in the form of the neurotransmitter glutamate, which is detected by a G protein-coupled receptor (GPCR) signal transduction cascade. Detection of glutamate by the GPCR Metabotropic glutamate receptor 6 results in closing of the TRPM1 channel. At the onset of light, glutamate release is halted and mGluR6 is deactivated; this results in opening of the TRPM1 channel, influx of sodium and calcium, and depolarization of the bipolar cell.
In addition to the retina, TRPM1 is also expressed in melanocytes, which are melanin-producing cells in the skin. The expression of TRPM1 is inversely correlated with melanoma aggressiveness, suggesting that it might suppress melanoma metastasis. However, subsequent work showed that a microRNA located in an intron of the TRPM1 gene, rather than the TRPM1 protein itself, is responsible for the tumor suppressor function. The expression of both TRPM1 and the microRNA are regulated by the Microphthalmia-associated transcription factor.
# Clinical significance
Mutations in TRPM1 are associated with congenital stationary night blindness in humans and coat spotting patterns in Appaloosa horses. | TRPM1
Transient receptor potential cation channel subfamily M member 1 is a protein that in humans is encoded by the TRPM1 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the transient receptor potential (TRP) family of non-selective cation channels. It is expressed in the retina, in a subset of bipolar cells termed ON bipolar cells.[4][5] These cells form synapses with either rods or cones, collecting signals from them. In the dark, the signal arrives in the form of the neurotransmitter glutamate, which is detected by a G protein-coupled receptor (GPCR) signal transduction cascade. Detection of glutamate by the GPCR Metabotropic glutamate receptor 6 results in closing of the TRPM1 channel. At the onset of light, glutamate release is halted and mGluR6 is deactivated; this results in opening of the TRPM1 channel, influx of sodium and calcium, and depolarization of the bipolar cell.[6][7]
In addition to the retina, TRPM1 is also expressed in melanocytes, which are melanin-producing cells in the skin. The expression of TRPM1 is inversely correlated with melanoma aggressiveness, suggesting that it might suppress melanoma metastasis.[8] However, subsequent work showed that a microRNA located in an intron of the TRPM1 gene, rather than the TRPM1 protein itself, is responsible for the tumor suppressor function.[9][10] The expression of both TRPM1 and the microRNA are regulated by the Microphthalmia-associated transcription factor.[11][12][13][9]
# Clinical significance
Mutations in TRPM1 are associated with congenital stationary night blindness in humans [14][15][16][17] and coat spotting patterns in Appaloosa horses.[18] | https://www.wikidoc.org/index.php/TRPM1 | |
fb0b0637ad87d1f8dbbdd8b7cb79cc60ac410e99 | wikidoc | TRPM2 | TRPM2
Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the TRPM2 gene.
# Function
The TRPM2 gene is highly expressed in the brain and was implicated by both genetic linkage studies in families and then by case control or trio allelic association studies in the genetic aetiology of bipolar affective disorder (Manic Depression).
The physiological role of TRPM2 is not well understood. It was shown to be involved in insulin secretion. In the immune cells it mediates parts of the responses to TNF-alpha. A role has been suggested for TRPM2 in activation of NLRP3 inflammasome, the dysregulation of which is strongly associated with a number of auto inflammatory and metabolic diseases, such as gout, obesity and diabetes. In the brain it is involved in the toxicity of amyloid beta, a protein associated with Alzheimer's disease.. In 2016, TRPM2 channel was strongly implicated in the detection of non-painful warm stimuli. Chun-Hsiang Tan and Peter McNaughton studied the responses of actual sensory neurons to thermal stimuli, then used an RNA-sequencing strategy to identify TRPM2 as genetically required for warmth detection in the non-noxious range of 33–38 °C.
# Structure
The protein encoded by this gene is a non-selective calcium-permeable cation channel and is part of the Transient Receptor Potential ion channel super family. The closest relative is the cold and menthol activated TRPM8 ion channel. While TRPM2 is not cold sensitive it is activated by heat. The TRPM2 ion channel is activated by free intracellular ADP-ribose in synergy with free intracellular calcium. ADP-Ribose is produced to by the enzyme PARP in response to oxidative stress and confers susceptibility to cell death. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. | TRPM2
Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the TRPM2 gene.
# Function
The TRPM2 gene is highly expressed in the brain and was implicated by both genetic linkage studies in families[1] and then by case control or trio allelic association studies in the genetic aetiology of bipolar affective disorder (Manic Depression).[2][3]
The physiological role of TRPM2 is not well understood. It was shown to be involved in insulin secretion.[4][5] In the immune cells it mediates parts of the responses to TNF-alpha.[6] A role has been suggested for TRPM2 in activation of NLRP3 inflammasome, the dysregulation of which is strongly associated with a number of auto inflammatory and metabolic diseases, such as gout, obesity and diabetes.[7] In the brain it is involved in the toxicity of amyloid beta, a protein associated with Alzheimer's disease.[8]. In 2016, TRPM2 channel was strongly implicated in the detection of non-painful warm stimuli. Chun-Hsiang Tan and Peter McNaughton studied the responses of actual sensory neurons to thermal stimuli, then used an RNA-sequencing strategy to identify TRPM2 as genetically required for warmth detection in the non-noxious range of 33–38 °C.[9]
# Structure
The protein encoded by this gene is a non-selective calcium-permeable cation channel and is part of the Transient Receptor Potential ion channel super family. The closest relative is the cold and menthol activated TRPM8 ion channel. While TRPM2 is not cold sensitive it is activated by heat.[4] The TRPM2 ion channel is activated by free intracellular ADP-ribose in synergy with free intracellular calcium.[10] ADP-Ribose is produced to by the enzyme PARP in response to oxidative stress and confers susceptibility to cell death. Several alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known.[11] | https://www.wikidoc.org/index.php/TRPM2 | |
7eaf5d925206643f212f8216f83044c571debb02 | wikidoc | TRPM3 | TRPM3
Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.
# Function
The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been -identified.
TRPM3 was shown to be activated by the neurosteroid pregnenolone sulphate in pancreatic beta cell. The activation causes calcium influx and subsequent insulin release, therefore it is suggested that TRPM3 modulates glucose homeostasis.
# TRPM3 Ligands
## Channel Blockers
- Mefenamic acid
- Citrus fruit flavonoids, E.g. Naringenin and hesperetin, as well as Ononetin (a deoxybenzoin).
## Agonist
- CIM0216 | TRPM3
Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.[1]
# Function
The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion. Alternatively spliced transcript variants encoding different isoforms have been -identified.[2]
TRPM3 was shown to be activated by the neurosteroid pregnenolone sulphate in pancreatic beta cell. The activation causes calcium influx and subsequent insulin release, therefore it is suggested that TRPM3 modulates glucose homeostasis.[3]
# TRPM3 Ligands
## Channel Blockers
- Mefenamic acid[4]
- Citrus fruit flavonoids, E.g. Naringenin and hesperetin, as well as Ononetin (a deoxybenzoin).[5]
## Agonist
- CIM0216 | https://www.wikidoc.org/index.php/TRPM3 | |
441f134351f77198e642ae93e11c48be63f86586 | wikidoc | TRPM5 | TRPM5
Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the TRPM5 gene.
# Function
TRPM5 is a calcium-activated non-selective cation channel that induces depolarization upon increases in intracellular calcium, it is a signal mediator in chemosensory cells. Channel activity is initiated by a rise in the intracellular calcium, and the channel permeates monovalent cations as K+ and Na+.
TRPM5 is a key component of taste transduction in the gustatory system of bitter, sweet and umami tastes being activated by high levels of intracellular calcium. It has also been targeted as a possible contributor to fat taste signaling. The calcium dependent opening of TRPM5 produces a depolarizing generator potential which leads to an action potential.
TRPM5 is expressed in pancreatic β-cells where it is involved in the signaling mechanism for insulin secretion. The potentiation of TRPM5 in the β-cells leads to increased insulin secretion and protects against the development of type 2 diabetes in mice. Further expression of TRPM5 can be found in tuft cells, solitary chemosensory cells and several other cell types in the body that have a sensory role.
# Drugs modulating TRPM5
The role of TRPM5 in the pancreatic β-cell makes it a target for the development of novel antidiabetic therapies.
## Agonists
- Steviol glycosides, the sweet compounds in the leaves of the Stevia rebaudiana plant, potentiate the calcium-induced activity of TRPM5. In this way they stimulate the glucose-induced insulin secretion from the pancreatic β-cell.
- Rutamarin, a phytochemical found in Ruta graveolens has been identified as an activator of several TRP channels, including TRPM5 and TRPV1 and inhibits the activity of TRPM8.
## Antagonists
Selective blocking agents of TRPM5 ion channels can be used to identify TRPM5 currents in primary cells. Most identified compounds show, however, a poor selectivity between TRPM4 and TRPM5 or other ion channels.
- TPPO or TriPhenylPhosphineOxide is the most selective blocker of TRPM5 however, its application suffers due to a poor solubility.
- Ketoconazole is an antifungal drug that inhibits TRPM5 activity.
- Flufenamic Acid is a NSAID drug that inhibits the activity of TRPM5 or TRPM4.
- Clotrimazole is an antifungal drug and reduces the currents through TRPM5.
- Nicotine inhibits the TRPM5 channel. Through the inhibition of TRPM5, the taste loss observed in people with a smoking habit can be explained. | TRPM5
Transient receptor potential cation channel subfamily M member 5 (TRPM5), also known as long transient receptor potential channel 5 is a protein that in humans is encoded by the TRPM5 gene.[1][2]
# Function
TRPM5 is a calcium-activated non-selective cation channel that induces depolarization upon increases in intracellular calcium, it is a signal mediator in chemosensory cells. Channel activity is initiated by a rise in the intracellular calcium, and the channel permeates monovalent cations as K+ and Na+.
TRPM5 is a key component of taste transduction in the gustatory system of bitter, sweet and umami tastes being activated by high levels of intracellular calcium. It has also been targeted as a possible contributor to fat taste signaling.[3][4] The calcium dependent opening of TRPM5 produces a depolarizing generator potential which leads to an action potential.[5]
TRPM5 is expressed in pancreatic β-cells[6] where it is involved in the signaling mechanism for insulin secretion. The potentiation of TRPM5 in the β-cells leads to increased insulin secretion and protects against the development of type 2 diabetes in mice.[7] Further expression of TRPM5 can be found in tuft cells,[8] solitary chemosensory cells and several other cell types in the body that have a sensory role.
# Drugs modulating TRPM5
The role of TRPM5 in the pancreatic β-cell makes it a target for the development of novel antidiabetic therapies.[9]
## Agonists
- Steviol glycosides, the sweet compounds in the leaves of the Stevia rebaudiana plant, potentiate the calcium-induced activity of TRPM5. In this way they stimulate the glucose-induced insulin secretion from the pancreatic β-cell.[7]
- Rutamarin, a phytochemical found in Ruta graveolens has been identified as an activator of several TRP channels, including TRPM5 and TRPV1 and inhibits the activity of TRPM8.[10]
## Antagonists
Selective blocking agents of TRPM5 ion channels can be used to identify TRPM5 currents in primary cells. Most identified compounds show, however, a poor selectivity between TRPM4 and TRPM5 or other ion channels.
- TPPO or TriPhenylPhosphineOxide is the most selective blocker of TRPM5 however, its application suffers due to a poor solubility.[11]
- Ketoconazole is an antifungal drug that inhibits TRPM5 activity.[12]
- Flufenamic Acid is a NSAID drug that inhibits the activity of TRPM5 or TRPM4.[13]
- Clotrimazole is an antifungal drug and reduces the currents through TRPM5.[13]
- Nicotine inhibits the TRPM5 channel. Through the inhibition of TRPM5, the taste loss observed in people with a smoking habit can be explained.[14] | https://www.wikidoc.org/index.php/TRPM5 | |
b864bd6b19f33457965852e6614d9ee517181ed9 | wikidoc | TRPM7 | TRPM7
Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7, is a human gene encoding a protein of the same name.
# Function
TRPs, mammalian homologs of the Drosophila transient receptor potential (trp) protein, are ion channels that are thought to mediate capacitative calcium entry into the cell. TRP-PLIK is a protein that is both an ion channel and a kinase. As a channel, it conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. As a kinase, it is capable of phosphorylating itself and other substrates. The kinase activity is necessary for channel function, as shown by its dependence on intracellular ATP and by the kinase mutants.
# Interactions
TRPM7 has been shown to interact with PLCB1 and PLCB2.
# Clinical relevance
Defects in this gene have been associated to magnesium deficiency in human microvascular endothelial cells. | TRPM7
Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7, is a human gene encoding a protein of the same name.
# Function
TRPs, mammalian homologs of the Drosophila transient receptor potential (trp) protein, are ion channels that are thought to mediate capacitative calcium entry into the cell. TRP-PLIK is a protein that is both an ion channel and a kinase. As a channel, it conducts calcium and monovalent cations to depolarize cells and increase intracellular calcium. As a kinase, it is capable of phosphorylating itself and other substrates. The kinase activity is necessary for channel function, as shown by its dependence on intracellular ATP and by the kinase mutants.[supplied by OMIM][1]
# Interactions
TRPM7 has been shown to interact with PLCB1[2] and PLCB2.[2]
# Clinical relevance
Defects in this gene have been associated to magnesium deficiency in human microvascular endothelial cells.[3] | https://www.wikidoc.org/index.php/TRPM7 | |
4c5aa6b8a63f56200d05ad19e53975e0f964680c | wikidoc | TRPM8 | TRPM8
Transient receptor potential cation channel subfamily M member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans.
# Structure
The TRPM8 channel is a homotetramer, composed of four identical subunits with a transmembrane domain with six helices (S1–6). The first four, S1–4, act as the voltage sensor and allow binding of menthol, icilin and similar channel agonists. S5 and S6 and a connecting loop, also part of the structure, make up the pore, a non-selective cation channel which consists of a highly conserved hydrophobic region, A range of diverse components are required for the high level of specificity in responding to result in ion flow to cold and menthol stimuli.
# Function
TRPM8 is an ion channel, upon activation it allows the entry of Na+ and Ca2+ ions to the cell that leads to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C- and A-delta) eventually leading to the sensation of cold and cold pain.
The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin whereas WS-12 and CPS-369 are the most selective agonists of TRPM8.
TRPM8 is also expressed in the prostate, lungs, and bladder where its function is not well understood.
## Role in the nervous system
The transient receptor potential channel (TRP) superfamily, which includes the menthol (TRPM8) and capsaicin receptors (TRPV1), serve a variety of functions in the peripheral and central nervous systems. In the peripheral nervous system, TRPs respond to stimuli from temperature, pressure, inflammatory agents, and receptor activation. Central nervous system roles of the receptors include neurite outgrowth, receptor signaling, and excitoxic cell death resulting from noxious stimuli.
McKemy et al., 2002 provided some of the first evidence for existence of a cold-activated receptor throughout the mammalian somatosensory system. Using calcium imaging and patch clamp based approaches, they showed a response in dorsal root ganglion (DRG) neurons that exposure to cold, 20 °C or cooler, lead to a response in calcium influx. This receptor was shown to respond to both cold temperatures, menthol, and similar now-known agonists of the TRPM8 receptor. It works in conjunction with the TRPV1 receptor to maintain a feasible threshold temperature range in which our cells are comfortable and our perception of these stimuli occurs at the spinal cord and brain, which integrate signals from different fibers of varying sensitivity to temperature. Application of menthol to skin or mucus membranes results directly in membrane depolarization, followed by calcium influx via voltage-dependent calcium channels, providing evidence for the role of TRPM8 and other TRP receptors to mediate our sensory interaction with the environment in response to cold in the same way as in response to menthol.
# Properties
## pH-sensitivity
In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions were shown to inhibit the TRPM8 Ca2+ response to menthol and icilin (an agonist of the menthol receptor). It is hypothesized the TRPV1 and TRPM8 receptors act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain.
## Sensitization
Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization. The primary consensus finding is that TRPM8 sensitization increases the sensation of cold pain, also known as cold hyperalgesia. An experiment was done in a double-blind two-way crossover study by applying 40% L-menthol to the forearm, using ethanol as a control. Activation of the TRPM8-receptor channel (the primary menthol receptor channel) resulted in increased sensitization to the menthol stimulus. To investigate the mechanisms of this sensitization, Wasner et al., 2004, performed A fiber conduction blockade of the superficial radial nerve in another group of subjects. This ended up reducing the menthol-induced sensation of cold and hyperalgesia because blocking A fiber conduction resulted in inhibition of a class of group C nerve fiber nociceptors needed to transduce the sensation of pain. They concluded menthol sensitizes cold-sensitive peripheral C nociceptors and activates cold-specific A delta fibers.
## Desensitization
As is common in response to many other sensory stimuli, much experimental evidence exists for the desensitization of human response of TRPM8 receptors to menthol. Testing involving administration of menthol and nicotine-containing cigarettes non-smokers, which induced what they classified as an irritant response, after initial sensitization, showed a declining response in subjects over time, lending itself to the incidence of desensitization. Ethanol, with similar irritant and desensitization properties, was used as a control for nicotine, to distinguish it from menthol-induced response. The menthol receptor was seen to sensitize or desensitize based on cellular conditions, and menthol produces increased activity in Ca2+-voltage gated channels that is not seen in ethanol, cyclohexanol and other irritant controls, suggestive of a specific molecular receptor. Dessirier et al., 2001, also claim the cross-desensitization of menthol receptors can occur by unknown molecular mechanisms, though they hypothesize the importance of Ca2+ in reducing cell excitability in a way similar to that in the capsaicin receptor.
Mutagenesis of protein kinase C phoshorylation sites in TRPM8 (wild type serines and threonines replaced by alanine in mutants) reduces the desensitizing response.
## Cross-desensitization
Cliff et al., 1994, performed a study to discover more about the properties of the menthol receptor and whether menthol had the ability to cross-desensitize with other chemical irritant receptors. Capsaicin was known to cross-desensitize with other irritant agonists, where the same information was not known about menthol. The study involved subjects swishing either menthol or capsaicin for an extended time at regular intevals. There were three significant conclusions about cross-desensitizing: 1) Both chemicals self-desensitize, 2) menthol receptors can desensitize in response to capsaicin, and, most novelly, 3) capsaicin receptors are desensitized in response to menthol.
# Ligands
## Agonists
In a search for compounds that activated the TRPM8 cold receptor, compounds that produce a cooling-sensation were sought out from the fragrance industries. Of 70 relevant compounds, the following 10 produced the associated -increase response in mTRPM8-transfected HEK293 cells used to identify agonists. Experimentally identified and commonly utilized agonists of the menthol receptor include linalool, geraniol, hydroxy-citronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag and Cooling Agent 10.
## Antagonists
BCTC, thio-BCTC, capsazepine and M8-An were identified as antagonists of the TRPM8 receptor. These antagonists physically block the receptor for cold and menthol, by binding to the S1-S4 voltage-sensing domain, preventing response.
- PF 05105679 cas: .
- M8 B
- AMTB
- 5-benzyloxytryptamine
# Clinical significance
Cold-patches have traditionally been used to induce analgesia or relief in pain which is caused as result of traumatic injuries. The underlying mechanism of cold-induced analgesia remained obscure until the discovery of TRPM8.
One research group has reported that TRPM8 is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibers.
Three independent research groups have reported that mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Many research groups, both in universities and pharmaceutical companies, are now actively involved in looking for selective TRPM8 ligands to be used as new generation of neuropathic analgesic drugs.
Low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions, whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.
TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain. Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models.
TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes. Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death.
## Role in cancer
TRPM8 channels may be a target for treating prostate cancer. TRPM8 is an androgen dependent Ca2+ channel necessary for prostate cancer cells to survive and grow. Immunfluorescence showed expression of the TRPM8 protein in the ER and plasma membrane of the androgen-responsive LNCaP cell line. TRPM8 was expressed in androgen-insensitive cells, but it was not shown to be needed for their survival. By knockout of TRPM8 with siRNAs targeting TRPM8 mRNAs, the necessity of the TRPM8 receptor was shown in the androgen-dependent cancer cells. This has useful implications in terms of gene therapy, as there are so few treatment options for men with prostate cancer. As an androgen-regulated protein whose function is lost as cancer develops in cells, the TRPM8 protein seems to be especially critical in regulating calcium levels and has recently been proposed as the focus of new drugs used to treat prostate cancer. | TRPM8
Transient receptor potential cation channel subfamily M member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene.[1][2] The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans.[1][3]
# Structure
The TRPM8 channel is a homotetramer, composed of four identical subunits with a transmembrane domain with six helices (S1–6). The first four, S1–4, act as the voltage sensor and allow binding of menthol, icilin and similar channel agonists. S5 and S6 and a connecting loop, also part of the structure, make up the pore, a non-selective cation channel which consists of a highly conserved hydrophobic region, A range of diverse components are required for the high level of specificity in responding to result in ion flow to cold and menthol stimuli.[4]
# Function
TRPM8 is an ion channel, upon activation it allows the entry of Na+ and Ca2+ ions to the cell that leads to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C- and A-delta) eventually leading to the sensation of cold and cold pain.[1]
The TRPM8 protein is expressed in sensory neurons, and it is activated by cold temperatures and cooling agents, such as menthol and icilin whereas WS-12 and CPS-369 are the most selective agonists of TRPM8.[5][6]
TRPM8 is also expressed in the prostate, lungs, and bladder where its function is not well understood.
## Role in the nervous system
The transient receptor potential channel (TRP) superfamily, which includes the menthol (TRPM8) and capsaicin receptors (TRPV1), serve a variety of functions in the peripheral and central nervous systems. In the peripheral nervous system, TRPs respond to stimuli from temperature, pressure, inflammatory agents, and receptor activation. Central nervous system roles of the receptors include neurite outgrowth, receptor signaling, and excitoxic cell death resulting from noxious stimuli.[7]
McKemy et al., 2002 provided some of the first evidence for existence of a cold-activated receptor throughout the mammalian somatosensory system.[1] Using calcium imaging and patch clamp based approaches, they showed a response in dorsal root ganglion (DRG) neurons that exposure to cold, 20 °C or cooler, lead to a response in calcium influx. This receptor was shown to respond to both cold temperatures, menthol, and similar now-known agonists of the TRPM8 receptor. It works in conjunction with the TRPV1 receptor to maintain a feasible threshold temperature range in which our cells are comfortable and our perception of these stimuli occurs at the spinal cord and brain, which integrate signals from different fibers of varying sensitivity to temperature. Application of menthol to skin or mucus membranes results directly in membrane depolarization, followed by calcium influx via voltage-dependent calcium channels, providing evidence for the role of TRPM8 and other TRP receptors to mediate our sensory interaction with the environment in response to cold in the same way as in response to menthol.[8]
# Properties
## pH-sensitivity
In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions were shown to inhibit the TRPM8 Ca2+ response to menthol and icilin (an agonist of the menthol receptor). It is hypothesized the TRPV1 and TRPM8 receptors act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain.[9]
## Sensitization
Numerous studies have been published investigating the effect of L-menthol application as a model for TRPM8-sensitization.[1][10] The primary consensus finding is that TRPM8 sensitization increases the sensation of cold pain, also known as cold hyperalgesia.[1][1] An experiment was done in a double-blind two-way crossover study by applying 40% L-menthol to the forearm, using ethanol as a control. Activation of the TRPM8-receptor channel (the primary menthol receptor channel) resulted in increased sensitization to the menthol stimulus. To investigate the mechanisms of this sensitization, Wasner et al., 2004, performed A fiber conduction blockade of the superficial radial nerve in another group of subjects. This ended up reducing the menthol-induced sensation of cold and hyperalgesia because blocking A fiber conduction resulted in inhibition of a class of group C nerve fiber nociceptors needed to transduce the sensation of pain. They concluded menthol sensitizes cold-sensitive peripheral C nociceptors and activates cold-specific A delta fibers.[1][3][11]
## Desensitization
As is common in response to many other sensory stimuli, much experimental evidence exists for the desensitization of human response of TRPM8 receptors to menthol.[1] Testing involving administration of menthol and nicotine-containing cigarettes non-smokers, which induced what they classified as an irritant response, after initial sensitization, showed a declining response in subjects over time, lending itself to the incidence of desensitization. Ethanol, with similar irritant and desensitization properties, was used as a control for nicotine, to distinguish it from menthol-induced response. The menthol receptor was seen to sensitize or desensitize based on cellular conditions, and menthol produces increased activity in Ca2+-voltage gated channels that is not seen in ethanol, cyclohexanol and other irritant controls, suggestive of a specific molecular receptor. Dessirier et al., 2001, also claim the cross-desensitization of menthol receptors can occur by unknown molecular mechanisms, though they hypothesize the importance of Ca2+ in reducing cell excitability in a way similar to that in the capsaicin receptor.[12]
Mutagenesis of protein kinase C phoshorylation sites in TRPM8 (wild type serines and threonines replaced by alanine in mutants) reduces the desensitizing response.[13]
## Cross-desensitization
Cliff et al., 1994, performed a study to discover more about the properties of the menthol receptor and whether menthol had the ability to cross-desensitize with other chemical irritant receptors. Capsaicin was known to cross-desensitize with other irritant agonists, where the same information was not known about menthol. The study involved subjects swishing either menthol or capsaicin for an extended time at regular intevals. There were three significant conclusions about cross-desensitizing: 1) Both chemicals self-desensitize, 2) menthol receptors can desensitize in response to capsaicin, and, most novelly, 3) capsaicin receptors are desensitized in response to menthol.[14]
# Ligands
## Agonists
In a search for compounds that activated the TRPM8 cold receptor, compounds that produce a cooling-sensation were sought out from the fragrance industries. Of 70 relevant compounds, the following 10 produced the associated [Ca2+]-increase response in mTRPM8-transfected HEK293 cells used to identify agonists. Experimentally identified and commonly utilized agonists of the menthol receptor include linalool, geraniol, hydroxy-citronellal, WS-3, WS-23, Frescolat MGA, Frescolat ML, PMD 38, Coolact P, M8-Ag and Cooling Agent 10.[9][10]
## Antagonists
BCTC, thio-BCTC, capsazepine and M8-An[15] were identified as antagonists of the TRPM8 receptor. These antagonists physically block the receptor for cold and menthol, by binding to the S1-S4 voltage-sensing domain, preventing response.[9]
- PF 05105679 cas: [1398583-31-7].
- M8 B
- AMTB
- 5-benzyloxytryptamine[16]
# Clinical significance
Cold-patches have traditionally been used to induce analgesia or relief in pain which is caused as result of traumatic injuries.[17] The underlying mechanism of cold-induced analgesia remained obscure until the discovery of TRPM8.
One research group has reported that TRPM8 is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons of afferent nerve fibers.[18]
Three independent research groups have reported that mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect cold temperatures.[19] Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia. These animals provide a great deal of insight into the molecular signaling pathways that participate in the detection of cold and painful stimuli. Many research groups, both in universities and pharmaceutical companies, are now actively involved in looking for selective TRPM8 ligands to be used as new generation of neuropathic analgesic drugs.[10][15]
Low concentrations of TRPM8 agonists such as menthol (or icilin) found to be antihyperalgesic in certain conditions,[20] whereas high concentrations of menthol caused both cold and mechanical hyperalgesia in healthy volunteers.[11]
TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain.[21] Furthermore, recently it was shown that TRPM8 antagonists are effective in reversing established pain in neuropathic and visceral pain models.[22][15]
TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes.[23] Furthermore, TRPM8 is upregulated in many prostate cancer cell lines and Dendreon/Genentech are pursuing an agonist approach to induce apoptosis and prostate cancer cell death.[24]
## Role in cancer
TRPM8 channels may be a target for treating prostate cancer. TRPM8 is an androgen dependent Ca2+ channel necessary for prostate cancer cells to survive and grow. Immunfluorescence showed expression of the TRPM8 protein in the ER and plasma membrane of the androgen-responsive LNCaP cell line. TRPM8 was expressed in androgen-insensitive cells, but it was not shown to be needed for their survival. By knockout of TRPM8 with siRNAs targeting TRPM8 mRNAs, the necessity of the TRPM8 receptor was shown in the androgen-dependent cancer cells. This has useful implications in terms of gene therapy, as there are so few treatment options for men with prostate cancer. As an androgen-regulated protein whose function is lost as cancer develops in cells, the TRPM8 protein seems to be especially critical in regulating calcium levels and has recently been proposed as the focus of new drugs used to treat prostate cancer.[25] | https://www.wikidoc.org/index.php/TRPM8 | |
c614d60b8094f95ee7e1ee8dcc88f2627ce83957 | wikidoc | TRPV1 | TRPV1
The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels.
The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception).
# Function
TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than 43 °C (Expression error: Missing operand for *. ); acidic conditions; capsaicin (the irritating compound in hot chili peppers); and allyl isothiocyanate, the pungent compound in mustard and wasabi. The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-oleyl-dopamine, and N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli.
## Sensitization
The sensitivity of TRPV1 to noxious stimuli, such as high temperatures, is not static. Upon tissue damage and the consequent inflammation, a number of inflammatory mediators, such as various prostaglandins and bradykinin, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli (hyperalgesia) or pain sensation in response to non-painful stimuli (allodynia). Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phosphorylation of TRPV1 by protein kinase C have been shown to play a role in sensitization of TRPV1. The cleavage of PIP2 by PLC-beta can result in disinhibition of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli.
## Desensitization
Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization. Extracellular calcium ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as calmodulin and calcineurin, and the decrease of PIP2, have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin.
# Clinical significance
## Peripheral nervous system
Treatment of pain is an unmet medical need costing billions of dollars every year. As a result of its involvement in nociception, TRPV1 has been a prime target for the development of novel pain reducers (analgesics). Two major strategies have been used:
## Antagonists
Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red. These agents could be useful when applied systemically. Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats. This provides evidence that TRPV1 is capsaicin's sole receptor.
In humans, drugs acting at TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.
The major roadblock for the usefulness of these drugs is their effect on body temperature (hyperthermia).
The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature by telling the body to "cool itself down". Without these signals, the body overheats. Likewise, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature. Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance. Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia. A second molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported. Recently, it was disclosed that clinical trials of two more TRPV1 antagonists, GRC 6211 and NGD 8243, have been stopped. Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Recent reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.
## Agonists
TRPV1 is activated by numerous agonists from natural sources. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, cause TRPV1 activity to decrease (desensitization), leading to alleviation of pain via the subsequent decrease in the TRPV1 mediated release of inflammatory molecules following exposures to noxious stimuli. Agonists can be applied locally to the painful area in various forms, generally as a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials. 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin. Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.
### Fatty acid metabolites
Certain metabolites of polyunsaturated fatty acids have been shown to stimulate cells in a TRPV1-dependent fashion. The metabolites of linoleic acid, including 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE), 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE, 9(S)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(S)-HODE), 9(R)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(R)-HODE), and their respective keto analogs, 13-oxoODE and 9-oxoODE (see 13-HODE and 9-HODE sections on Direct actions), activate peripheral and central mouse pain sensing neurons. Reports disagree on the potencies of these metabolites with, for example, the most potent one, 9(S)-HODE, requiring at least 10 micromoles/liter. or a more physiological concentration of 10 nanomoles/liter to activate TRPV1 in rodent neurons. The TRPV1-dependency of these metabolites' activities appears to reflect their direct interaction with TPRV1. Although relatively weak agonists of TRPV1 in comparison to anandamide, these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents and to cause injury to airway epithelial cells and thereby to contribute to asthma disease in mice and therefore possibly humans. Certain arachidonic acid metabolites, including 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (see 20-Hydroxyeicosatetraenoic acid) and 12(S)-hydroperoxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HpETE), 12(S)-hydroxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HETE (see 12-HETE), hepoxilin A3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) likewise activate TRPV1 and may thereby contribute to tactile hyperalgesia and allodynia (see Hepoxilin#Pain perception).
Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716), has been associated with ACE inhibitor-induced cough in humans.
Resolvin E1 (RvE1), RvD2 (see resolvins), neuroprotectin D1 (NPD1), and maresin 1 (Mar1) are metabolites of the omega 3 fatty acids, eicosapentaenoic acid (for RvE1) or docosahexaenoic acid (for RvD2, NPD1, and Mar1). These metabolites are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV1, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on the neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down-regulate TRPV1 and thereby pain perception.
### Fatty acid conjugates
N-Arachidonoyl dopamine, a endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC50 of approximately of 50 nM.
N-Oleyl-dopamine, another endogenous agonist, binds bind to human VR1 with an Ki of 36 Nm.
Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors.
AM404—an active metabolite of paracetamol—that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist.
The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors. TRPV1 colocalizes with CB1 receptors and CB2 receptors in sensory and brain neurons respectively, and other plant-cannabinoids like CBN, CBG, CBC, THCV, and CBDV are also agonists of this ion channel.
## Central nervous system
TRPV1 is also expressed at high levels in the central nervous system and has been proposed as a target for treatment not only of pain but also for other conditions such as anxiety.
Furthermore, TRPV1 appears to mediate long-term synaptic depression (LTD) in the hippocampus. LTD has been linked to a decrease in the ability to make new memories, unlike its opposite long-term potentiation (LTP), which aids in memory formation. A dynamic pattern of LTD and LTP occurring at many synapses provides a code for memory formation. Long-term depression and subsequent pruning of synapses with reduced activity is an important aspect of memory formation. In rat brain slices, activation of TRPV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD. In the brainstem (solitary tract nucleus), TRPV1 controls the asynchronous and spontaneous release of glutamate from unmyelinated cranial visceral afferents - release processes that are active at normal temperatures and hence quite distinct from TRPV1 responses in painful heat. Hence, there may be therapeutic potential in modulating TRPV1 in the central nervous system, perhaps as a treatment for epilepsy (TRPV1 is already a target in the peripheral nervous system for pain relief).
# Interactions
TRPV1 has been shown to interact with:
- CALM1,
- SNAPAP, and
- SYT9.
- CBD
- AEA
# Discovery
The dorsal root ganglion (DRG) neurons of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin. The research group of David Julius, therefore, created a cDNA library of genes expressed in dorsal root ganglion neurons, expressed the clones in HEK 293 cells, and looked for cells that respond to capsaicin with calcium influx (which HEK-293 normally not do). After several rounds of screening and dividing the library, a single clone encoding the TRPV1 channel was finally identified in 1997. It was the first TRPV channel to be identified. | TRPV1
The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group.[1][2] This protein is a member of the TRPV group of transient receptor potential family of ion channels.[3]
The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception).
# Function
TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than 43 °C (Expression error: Missing operand for *. ); acidic conditions; capsaicin (the irritating compound in hot chili peppers); and allyl isothiocyanate, the pungent compound in mustard and wasabi.[4] The activation of TRPV1 leads to a painful, burning sensation. Its endogenous activators include: low pH (acidic conditions), the endocannabinoid anandamide, N-oleyl-dopamine, and N-arachidonoyl-dopamine. TRPV1 receptors are found mainly in the nociceptive neurons of the peripheral nervous system, but they have also been described in many other tissues, including the central nervous system. TRPV1 is involved in the transmission and modulation of pain (nociception), as well as the integration of diverse painful stimuli.[5][6]
## Sensitization
The sensitivity of TRPV1 to noxious stimuli, such as high temperatures, is not static. Upon tissue damage and the consequent inflammation, a number of inflammatory mediators, such as various prostaglandins and bradykinin, are released. These agents increase the sensitivity of nociceptors to noxious stimuli. This manifests as an increased sensitivity to painful stimuli (hyperalgesia) or pain sensation in response to non-painful stimuli (allodynia). Most sensitizing pro-inflammatory agents activate the phospholipase C pathway. Phosphorylation of TRPV1 by protein kinase C have been shown to play a role in sensitization of TRPV1. The cleavage of PIP2 by PLC-beta can result in disinhibition of TRPV1 and, as a consequence, contribute to the sensitivity of TRPV1 to noxious stimuli.
## Desensitization
Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization. Extracellular calcium ions are required for this phenomenon, thus influx of calcium and the consequential increase of intracellular calcium mediate this effect. Various signaling pathways such as calmodulin and calcineurin, and the decrease of PIP2, have been implicated in desensitization of TRPV1. Desensitization of TRPV1 is thought to underlie the paradoxical analgesic effect of capsaicin.
# Clinical significance
## Peripheral nervous system
Treatment of pain is an unmet medical need costing billions of dollars every year. As a result of its involvement in nociception, TRPV1 has been a prime target for the development of novel pain reducers (analgesics). Two major strategies have been used:
## Antagonists
Antagonists block TRPV1 activity, thus reducing pain. Identified antagonists include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red.[1] These agents could be useful when applied systemically.[7] Numerous TRPV1 antagonists have been developed by pharmaceutical companies. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats.[8] This provides evidence that TRPV1 is capsaicin's sole receptor.[9]
In humans, drugs acting at TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.[10]
The major roadblock for the usefulness of these drugs is their effect on body temperature (hyperthermia).
The role of TRPV1 in the regulation of body temperature has emerged in the last few years. Based on a number of TRPV-selective antagonists' causing an increase in body temperature (hyperthermia), it was proposed that TRPV1 is tonically active in vivo and regulates body temperature[11] by telling the body to "cool itself down". Without these signals, the body overheats. Likewise, this explains the propensity of capsaicin (a TRPV1 agonist) to cause sweating (i.e.: a signal to reduce body temperature). In a recent report, it was found that tonically active TRPV1 channels are present in the viscera and keep an ongoing suppressive effect on body temperature.[12] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance [13] Experiments have shown that TRPV1 blockade increases body temperature in multiple species, including rodents and humans, suggesting that TRPV1 is involved in body temperature maintenance.[11] Recently, AMG 517, a highly selective TRPV1 antagonist was dropped out of clinical trials due to the undesirable level of hyperthermia.[14] A second molecule, SB-705498, was also evaluated in the clinic but its effect on body temperature was not reported.[15] Recently, it was disclosed that clinical trials of two more TRPV1 antagonists, GRC 6211 and NGD 8243, have been stopped. Post translational modification of TRPV1 protein by its phosphorylation is critical for its functionality. Recent reports published from NIH suggest that Cdk5-mediated phosphorylation of TRPV1 is required for its ligand-induced channel opening.[16]
## Agonists
TRPV1 is activated by numerous agonists from natural sources.[17] Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, upon prolonged application, cause TRPV1 activity to decrease (desensitization), leading to alleviation of pain via the subsequent decrease in the TRPV1 mediated release of inflammatory molecules following exposures to noxious stimuli. Agonists can be applied locally to the painful area in various forms, generally as a patch or an ointment. Numerous capsaicin-containing creams are available over the counter, containing low concentrations of capsaicin (0.025 - 0.075%). It is debated whether these preparations actually lead to TRPV1 desensitization; it is possible that they act via counter-irritation. Novel preparations containing higher capsaicin concentration (up to 10%) are under clinical trials.[18] 8% capsaicin patches have recently become available for clinical use, with supporting evidence demonstrating that a 30-minute treatment can provide up to 3 months analgesia by causing regression of TRPV1-containing neurons in the skin.[19] Currently, these treatments must be re-administered on a regular (albeit infrequent) schedule in order to maintain their analgesic effects.
### Fatty acid metabolites
Certain metabolites of polyunsaturated fatty acids have been shown to stimulate cells in a TRPV1-dependent fashion. The metabolites of linoleic acid, including 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE), 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE, 9(S)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(S)-HODE), 9(R)-hydroxy-10(E),12(Z)-octadecadienoic acid (9(R)-HODE), and their respective keto analogs, 13-oxoODE and 9-oxoODE (see 13-HODE and 9-HODE sections on Direct actions), activate peripheral and central mouse pain sensing neurons. Reports disagree on the potencies of these metabolites with, for example, the most potent one, 9(S)-HODE, requiring at least 10 micromoles/liter.[20] or a more physiological concentration of 10 nanomoles/liter[21] to activate TRPV1 in rodent neurons. The TRPV1-dependency of these metabolites' activities appears to reflect their direct interaction with TPRV1. Although relatively weak agonists of TRPV1 in comparison to anandamide,[20] these linoleate metabolites have been proposed to act through TRPV1 in mediating pain perception in rodents[21][22][23] and to cause injury to airway epithelial cells and thereby to contribute to asthma disease[24] in mice and therefore possibly humans. Certain arachidonic acid metabolites, including 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid (see 20-Hydroxyeicosatetraenoic acid)[25] and 12(S)-hydroperoxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HpETE), 12(S)-hydroxy-5Z,8Z,10E,12S,14Z-eicosatetraenoic acid (12(S)-HETE (see 12-HETE), hepoxilin A3 (i.e. 8R/S-hydroxy-11,12-oxido-5Z,9E,14Z-eicosatrienoic acid) and HxB3 (i.e. 10R/S-hydroxy-11,12-oxido-5Z,8Z,14Z-eicosatrienoic acid) likewise activate TRPV1 and may thereby contribute to tactile hyperalgesia and allodynia (see Hepoxilin#Pain perception).[26][27][28]
Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that another arachidonic acid metabolite, Prostaglandin E2, operates through its prostaglandin EP3 G protein coupled receptor to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716[29]), has been associated with ACE inhibitor-induced cough in humans.[30][31]
Resolvin E1 (RvE1), RvD2 (see resolvins), neuroprotectin D1 (NPD1), and maresin 1 (Mar1) are metabolites of the omega 3 fatty acids, eicosapentaenoic acid (for RvE1) or docosahexaenoic acid (for RvD2, NPD1, and Mar1). These metabolites are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV1, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on the neurons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down-regulate TRPV1 and thereby pain perception.[32][33][34][35][36]
### Fatty acid conjugates
N-Arachidonoyl dopamine, a endocannabinoid found in the human CNS, structurally similar to capsaicin, activates the TRPV1 channel with an EC50 of approximately of 50 nM.[6]
N-Oleyl-dopamine, another endogenous agonist, binds bind to human VR1 with an Ki of 36 Nm.[37]
Another endocannabinoid anandamide has also been shown to act on TRPV1 receptors.[38]
AM404—an active metabolite of paracetamol—that serves as an anandamide reuptake inhibitor and COX inhibitor also serves as a potent TRPV1 agonist.[39]
The plant-biosynthesized cannabinoid cannabidiol also shows "either direct or indirect activation" of TRPV1 receptors.[40] TRPV1 colocalizes with CB1 receptors and CB2 receptors in sensory and brain neurons respectively, and other plant-cannabinoids like CBN, CBG, CBC, THCV, and CBDV are also agonists of this ion channel.[41]
## Central nervous system
TRPV1 is also expressed at high levels in the central nervous system and has been proposed as a target for treatment not only of pain but also for other conditions such as anxiety.[42]
Furthermore, TRPV1 appears to mediate long-term synaptic depression (LTD) in the hippocampus.[43] LTD has been linked to a decrease in the ability to make new memories, unlike its opposite long-term potentiation (LTP), which aids in memory formation. A dynamic pattern of LTD and LTP occurring at many synapses provides a code for memory formation. Long-term depression and subsequent pruning of synapses with reduced activity is an important aspect of memory formation. In rat brain slices, activation of TRPV1 with heat or capsaicin induced LTD while capsazepine blocked capsaicin's ability to induce LTD.[43] In the brainstem (solitary tract nucleus), TRPV1 controls the asynchronous and spontaneous release of glutamate from unmyelinated cranial visceral afferents - release processes that are active at normal temperatures and hence quite distinct from TRPV1 responses in painful heat.[44] Hence, there may be therapeutic potential in modulating TRPV1 in the central nervous system, perhaps as a treatment for epilepsy (TRPV1 is already a target in the peripheral nervous system for pain relief).
# Interactions
TRPV1 has been shown to interact with:
- CALM1,[45]
- SNAPAP,[46] and
- SYT9.[46]
- CBD[47]
- AEA[47]
# Discovery
The dorsal root ganglion (DRG) neurons of mammals were known to express a heat-sensitive ion channel that could be activated by capsaicin.[48] The research group of David Julius, therefore, created a cDNA library of genes expressed in dorsal root ganglion neurons, expressed the clones in HEK 293 cells, and looked for cells that respond to capsaicin with calcium influx (which HEK-293 normally not do). After several rounds of screening and dividing the library, a single clone encoding the TRPV1 channel was finally identified in 1997. It was the first TRPV channel to be identified.[1] | https://www.wikidoc.org/index.php/TRPV1 | |
aa637f328806a1a672e6044262bdb09679b59ba4 | wikidoc | TRPV2 | TRPV2
Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.
# TRP subfamily
The vanilloid TRP subfamily (TRPV) named after the vanilloid receptor 1 consist of six members, four of them (TRPV1-TRPV4) have been related to thermal sensation. TRPV2 shares 50% of its homology with TRPV1. Compared to TRPV1 channels, TRPV2 channels do not open in response to vanilloids like capsaicin or thermal stimuli around 43 °C. This may be due to the composition of the ankyrin repeat domains in TRPV2, which are different than those in TRPV1. However, TRPV2 channels can open by noxious temperatures greater than 52 °C. TRPV2 initially was characterized as a noxious heat sensor channel, but more evidence suggest its importance in various osmosensory and mechanosensory mechanisms. The channel can open in response to a variety of stimuli including hormones, growth factors, mechanical stretching, heat, osmotic swelling, lysophospholipids, and cannabinoids. These channels are expressed in medium to large diameter neurons, motor neurons, and other non-neuronal tissues like the heart and lungs, which indicates its versatile function. The channel has an important role for basic cell function including contraction, cell proliferation, and cell death. The same channel can have different functions depending on the type of tissue. Other roles of TRPV2 continue to be explored in an attempt to define the role of translocation of TRPV2 by growth factors.
# Discovery
TRPV2 was independently discovered by two research groups and described in 1999. It was identified in the lab of David Julius as a close homolog of TRPV1, known as the first identified thermosensitive ion channel. Itaru Kojima from Gunma University was looking for a protein which is responsible for the entry of calcium into cells in response to insulin-like growth factor-1 (IGF-1). Upon stimulation of cells with IGF-1, it was discovered that TRPV2 translocates towards and integrates into the cell membrane and increases intracellular calcium concentrations.
# Structure
TRPV2 channel has a similar structure to potassium channels, which are the largest ion channel family. This channel is composed of six transmembrane spanning regions (S1-S6) with a pore forming loop between S5 and S6. The pore forming loop also defines the selectivity filter, which determines the ions that are able to enter the channel. The S1-S4 region, as well as the N and C terminals of the protein, is important in reference to the gating of the channel. Although TRPV2 is a nonspecific cation channel, it is more permeable to calcium ions; calcium is an intracellular messenger and plays a very important role in a variety of different cellular processes. At rest, the pore channel is closed; in the activated state, the channel opens, allowing the influx of sodium and calcium ions that initiates an action potential.
# Species homology
The TRPV subfamily of channels of 1 through 4 have unique functions. One important variation is that these channels trigger cellular signaling pathways via non-selective cation flux, making them unique. Specifically, the TRPV2 channel has structural similarities amongst the other members of the TRPV family. For instance, the channel consists of six transmembrane domains and a pore forming loop between S5 and S6. Within the human genome, putative homologs can be found. This suggests that the amino acids and proteins coded come from a common ancestor where their structures are conserved in function.
Among the subfamily, TRPV2 and TRPV1 share 50% of their sequence identity not only in humans, but in rats as well. The rat TRPV2 can be comparable to that of humans because they exhibit similar surface localization among one another. Each channel possesses ATP binding regions and the 50% sequence identity between TRPV1 and TRPV2 suggests that both channel’s Ankyrin repeat domain (ARD) bind to different regulatory ligands as well. The channels structure can be observed as similar to that of potassium channels. In knockout mice, the physiological thermal responses show similar activation to wild-type mice. On top of that, humans, rats, and mice are considered orthologues.
# Tissue distribution
## Homo sapiens
In homo sapiens, there is broad expression of TRPV2 in the lymph nodes, spleen, lung, appendix, and placenta; it is mostly expressed in the lungs. TRPV2 is majorly in a subpopulation of medium to large sensory neurons, as well as being distributed in the brain and spinal cord. The mRNA expression of TRPV2 is also found in human pulmonary and umbilical vein endothelial cells. Based on mRNA expression of TRPV2 in mice, it is also speculated that it is expressed in arterial muscle cells, which can then be influenced by blood pressure; though it was evident that TRPV2 expression was localized in the intracellular area, some growth factors localized it to the plasma cell membrane. In circulatory organs, studies and data suggest that TRPV2 may be a mechanosensor, meaning that it can sense changes in external stimuli; the mechanisms involved in opening TRPV2 by membrane stretching or hypoosmotic cell swelling have not yet been determined.
## Mus musculus
In mus musculus (house mouse), TRPV2 functions as a protein coding gene. There is broad expression of TRPV2 in the thymus, placenta, cerebellum, and spleen; it is most commonly expressed in the thymus. The thymus is a lymphoid organ involved in the function of the immune system, where T cells mature. T cells are an important component to the adaptive immune system, because it is where the body adapts to foreign substances; this demonstrates TRPV2’s importance in the immune system. TRPV2 in mus musculus is also activated by hypo-osmolarity and cell stretching, indicating that TRPV2 plays a role in mechanotransduction in mice as well. In experiments with knockout mice (TRPV2KO mice), it was found that TRPV2 is expressed in brown adipocytes and in brown adipose tissue (BAT). It can be concluded that TRPV2 plays a role in BAT thermogenesis in mice, since it was found that a lack of TRPV2 impairs this thermogenesis in BAT; given these results, this could be a target for human obesity therapy.
## Rattus norvegicus
In rattus norvegicus (Norway rat), there is broad expression of TRPV2 in the adrenal glands and the lungs, being most present in the adrenal glands. TRPV2 is also present in the thymus and spleen, but not in high amounts. Without using any external growth factors, TRPV2 is highly specific to the plasma cell membrane in rat adult dorsal root ganglions, cerebral cortex, and arterial muscle cells.
# Clinical significance
## Cancer
TRPV2 plays a role in negative homeostatic control of excess cell proliferation by inducing apoptosis (programmed cell death). This is accomplished predominantly through the Fas pathway, also known as the death-inducing signaling complex. Activation of TRPV2 by growth factors and hormones induces the receptor to translocate from intracellular compartments to the plasma membrane, which initiates the development of death signals. An example of the role of TRPV2 in apoptosis is its expression in the bladder cancer t24 cell line. TRPV2 in bladder cancer leads to apoptosis through the influx of calcium ions through the TPRV2 channel. In some tumors, the over-expression of TRPV2 can lead to abnormal signaling pathways that drives unchecked cell proliferation and resistance to apoptotic stimuli. The over-expression of TRPV2 has been linked to several cancer types and cell lines. TRPV2 is expressed in human HepG2 cells, a cell line containing human liver carcinogenic cells. Heat allows for calcium entry into these cells through TRPV2 channels, which aid in the maintenance of these cells. TRPV2 also negatively affects patients with gliomas. TRPV2 in carcinogenic glial cells leads to resistance to apoptotic cell death, leading to harmful, carcinogenic cell survival.
## Immunity
TRPV2 is expressed in the spleen, lymphocytes, and myeloid cells including granulocytes, macrophages and mast cells. Among these cell types, TRPV2 mediates cytokine release, phagocytosis, endocytosis, podosome assembly, and inflammation. The influx of calcium seems to play an important role in these functions. Mast cells are leukocytes (white blood cells) rich in histamine which are able to respond to a variety of stimuli, often initiating inflammatory and/or allergic responses. The responses generated by mast cells rely on the calcium influx in the plasma membrane with the help of channels. Surface localization of the TRPV2 protein along with coupling of the protein to calcium and proinflammatory degranulation have been found in mast cells. The activation of TRPV2 in high temperatures permits calcium ion influx, inducing the release of proinflammatory factors. Therefore, TRPV2 is essential in mast cell degranulation as a result of its response to heat.
Immune cells are also able to kill pathogens by binding to them and engulfing them in a process known as phagocytosis. In macrophages TRPV2 recruitment toward the phagosome is regulated by PI3k signaling, protein kinase C, akt kinase, and Src kinases. They are able to locate these microbes through chemotaxis which is TRPV2 mediated. When the pathogen is endocytosed it is degraded then presented on the membrane of antigen presenting cells (i.e macrophages). Macrophages present these antigens to T cells via a major histocompatibility complex (MHC). The region between the MHC-peptide and the T cell receptor is known as the immunosynapse. TRPV2 channels are highly concentrated in this region. When these two cells interact, it allows calcium to diffuse through the TRPV2 channel. TRPV2 mRNA has been detected in CD4+ and CD8+ T cells as well as in human B lymphocytes. TRPV2 is one type of ion channel that directs T cell activation, proliferation, and defense mechanisms. If the TRPV2 channel were absent or not functioning properly in T cells, T cell receptor signaling would not be optimal. TRPV2 also acts as a transmembrane protein on the surface of B cells, negatively controlling B cell activation. Abnormal TRPV2 expression has been reported in hematological diseases including multiple myeloma, myelodysplastic syndrome, Burkitt lymphoma, and acute myeloid leukemia.
## Metabolic
TRPV2 seems to be essential in glucose homeostasis. It is highly expressed in MIN6 cells, which is a β-cell. These cell types are known for releasing insulin, a molecule that functions to keep glucose levels low. Under unstimulated conditions, TRPV2 is localized in the cytoplasm. Activation causes the channel to translocate to the plasma membrane. This triggers the influx of calcium resulting in insulin secretion.
## Cardiovascular
TRPV2 is very important in the structure and function of cardiomyocytes (heart cells). Compared to skeletal muscles, TRPV2 is expressed 10 times as high in cardiomyocytes and is important in current conduction. TRPV2 has been shown to be involved in stretch-dependent responses in heart cells. TRPV2 expression is concentrated in intercalated discs which allows the synchronous contraction of cardiomyocytes. Abnormal expression of TRPV2 results in reduced shortening length, shortening rate, and lengthening rate which ultimately compromise cardiac contractile function.
## Central nervous system
The cannabis constituent, cannabidiol (CBD), is a compound that acts in the release of neurotransmitters in the brain (part of the class of chemicals called cannabinoids) and has been researched for its positive effects in the treatment of epilepsy. CBD is able to bind to TRPV2 (as only plant-derived cannabinoids are TRPV2 agonists), which results in a reduction of epileptic activity and, consequently, a decrease in mortality. Recent research demonstrated that, in vitro, CBD decreases epileptiform local field potential burst amplitude and burst duration and increases burst frequency. Testing CBD in vivo indicated a decrease in severe seizure incidence (an increase in anticonvulsant effects). Therefore, CBD increases the expression and activation of TRPV2, resulting in the inhibition of epileptic activity both in vitro and in vivo. | TRPV2
Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene.[1][2] TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.
# TRP subfamily
The vanilloid TRP subfamily (TRPV) named after the vanilloid receptor 1 consist of six members, four of them (TRPV1-TRPV4) have been related to thermal sensation. TRPV2 shares 50% of its homology with TRPV1. Compared to TRPV1 channels, TRPV2 channels do not open in response to vanilloids like capsaicin or thermal stimuli around 43 °C.[3] This may be due to the composition of the ankyrin repeat domains in TRPV2, which are different than those in TRPV1. However, TRPV2 channels can open by noxious temperatures greater than 52 °C.[3] TRPV2 initially was characterized as a noxious heat sensor channel, but more evidence suggest its importance in various osmosensory and mechanosensory mechanisms. The channel can open in response to a variety of stimuli including hormones, growth factors, mechanical stretching, heat, osmotic swelling, lysophospholipids, and cannabinoids. These channels are expressed in medium to large diameter neurons, motor neurons, and other non-neuronal tissues like the heart and lungs, which indicates its versatile function. The channel has an important role for basic cell function including contraction, cell proliferation, and cell death. The same channel can have different functions depending on the type of tissue. Other roles of TRPV2 continue to be explored in an attempt to define the role of translocation of TRPV2 by growth factors.
# Discovery
TRPV2 was independently discovered by two research groups and described in 1999. It was identified in the lab of David Julius as a close homolog of TRPV1, known as the first identified thermosensitive ion channel.[1] Itaru Kojima from Gunma University was looking for a protein which is responsible for the entry of calcium into cells in response to insulin-like growth factor-1 (IGF-1). Upon stimulation of cells with IGF-1, it was discovered that TRPV2 translocates towards and integrates into the cell membrane and increases intracellular calcium concentrations.
# Structure
TRPV2 channel has a similar structure to potassium channels, which are the largest ion channel family. This channel is composed of six transmembrane spanning regions (S1-S6) with a pore forming loop between S5 and S6.[4] The pore forming loop also defines the selectivity filter, which determines the ions that are able to enter the channel. The S1-S4 region, as well as the N and C terminals of the protein, is important in reference to the gating of the channel. Although TRPV2 is a nonspecific cation channel, it is more permeable to calcium ions; calcium is an intracellular messenger and plays a very important role in a variety of different cellular processes. At rest, the pore channel is closed; in the activated state, the channel opens, allowing the influx of sodium and calcium ions that initiates an action potential.
# Species homology
The TRPV subfamily of channels of 1 through 4 have unique functions. One important variation is that these channels trigger cellular signaling pathways via non-selective cation flux, making them unique. Specifically, the TRPV2 channel has structural similarities amongst the other members of the TRPV family. For instance, the channel consists of six transmembrane domains and a pore forming loop between S5 and S6.[5] Within the human genome, putative homologs can be found. This suggests that the amino acids and proteins coded come from a common ancestor where their structures are conserved in function.
Among the subfamily, TRPV2 and TRPV1 share 50% of their sequence identity not only in humans, but in rats as well. The rat TRPV2 can be comparable to that of humans because they exhibit similar surface localization among one another. Each channel possesses ATP binding regions and the 50% sequence identity between TRPV1 and TRPV2 suggests that both channel’s Ankyrin repeat domain (ARD) bind to different regulatory ligands as well.[5] The channels structure can be observed as similar to that of potassium channels. In knockout mice, the physiological thermal responses show similar activation to wild-type mice. On top of that, humans, rats, and mice are considered orthologues.
# Tissue distribution
## Homo sapiens
In homo sapiens, there is broad expression of TRPV2 in the lymph nodes, spleen, lung, appendix, and placenta; it is mostly expressed in the lungs.[6] TRPV2 is majorly in a subpopulation of medium to large sensory neurons, as well as being distributed in the brain and spinal cord.[7] The mRNA expression of TRPV2 is also found in human pulmonary and umbilical vein endothelial cells.[7] Based on mRNA expression of TRPV2 in mice, it is also speculated that it is expressed in arterial muscle cells, which can then be influenced by blood pressure; though it was evident that TRPV2 expression was localized in the intracellular area, some growth factors localized it to the plasma cell membrane.[7] In circulatory organs, studies and data suggest that TRPV2 may be a mechanosensor, meaning that it can sense changes in external stimuli; the mechanisms involved in opening TRPV2 by membrane stretching or hypoosmotic cell swelling have not yet been determined.[7]
## Mus musculus
In mus musculus (house mouse), TRPV2 functions as a protein coding gene. There is broad expression of TRPV2 in the thymus, placenta, cerebellum, and spleen; it is most commonly expressed in the thymus.[8] The thymus is a lymphoid organ involved in the function of the immune system, where T cells mature. T cells are an important component to the adaptive immune system, because it is where the body adapts to foreign substances; this demonstrates TRPV2’s importance in the immune system. TRPV2 in mus musculus is also activated by hypo-osmolarity and cell stretching, indicating that TRPV2 plays a role in mechanotransduction in mice as well.[8] In experiments with knockout mice (TRPV2KO mice), it was found that TRPV2 is expressed in brown adipocytes and in brown adipose tissue (BAT). It can be concluded that TRPV2 plays a role in BAT thermogenesis in mice, since it was found that a lack of TRPV2 impairs this thermogenesis in BAT; given these results, this could be a target for human obesity therapy.[9]
## Rattus norvegicus
In rattus norvegicus (Norway rat), there is broad expression of TRPV2 in the adrenal glands and the lungs, being most present in the adrenal glands. TRPV2 is also present in the thymus and spleen, but not in high amounts. Without using any external growth factors, TRPV2 is highly specific to the plasma cell membrane in rat adult dorsal root ganglions, cerebral cortex, and arterial muscle cells.[7]
# Clinical significance
## Cancer
TRPV2 plays a role in negative homeostatic control of excess cell proliferation by inducing apoptosis (programmed cell death).[10] This is accomplished predominantly through the Fas pathway, also known as the death-inducing signaling complex. Activation of TRPV2 by growth factors and hormones induces the receptor to translocate from intracellular compartments to the plasma membrane, which initiates the development of death signals.[11] An example of the role of TRPV2 in apoptosis is its expression in the bladder cancer t24 cell line. TRPV2 in bladder cancer leads to apoptosis through the influx of calcium ions through the TPRV2 channel. In some tumors, the over-expression of TRPV2 can lead to abnormal signaling pathways that drives unchecked cell proliferation and resistance to apoptotic stimuli. The over-expression of TRPV2 has been linked to several cancer types and cell lines. TRPV2 is expressed in human HepG2 cells, a cell line containing human liver carcinogenic cells. Heat allows for calcium entry into these cells through TRPV2 channels, which aid in the maintenance of these cells.[12] TRPV2 also negatively affects patients with gliomas. TRPV2 in carcinogenic glial cells leads to resistance to apoptotic cell death, leading to harmful, carcinogenic cell survival.[13]
## Immunity
TRPV2 is expressed in the spleen, lymphocytes, and myeloid cells including granulocytes, macrophages and mast cells. Among these cell types, TRPV2 mediates cytokine release, phagocytosis, endocytosis, podosome assembly, and inflammation.[14] The influx of calcium seems to play an important role in these functions. Mast cells are leukocytes (white blood cells) rich in histamine which are able to respond to a variety of stimuli, often initiating inflammatory and/or allergic responses. The responses generated by mast cells rely on the calcium influx in the plasma membrane with the help of channels. Surface localization of the TRPV2 protein along with coupling of the protein to calcium and proinflammatory degranulation have been found in mast cells. The activation of TRPV2 in high temperatures permits calcium ion influx, inducing the release of proinflammatory factors. Therefore, TRPV2 is essential in mast cell degranulation as a result of its response to heat.[15]
Immune cells are also able to kill pathogens by binding to them and engulfing them in a process known as phagocytosis. In macrophages TRPV2 recruitment toward the phagosome is regulated by PI3k signaling, protein kinase C, akt kinase, and Src kinases.[16] They are able to locate these microbes through chemotaxis which is TRPV2 mediated. When the pathogen is endocytosed it is degraded then presented on the membrane of antigen presenting cells (i.e macrophages). Macrophages present these antigens to T cells via a major histocompatibility complex (MHC). The region between the MHC-peptide and the T cell receptor is known as the immunosynapse. TRPV2 channels are highly concentrated in this region. When these two cells interact, it allows calcium to diffuse through the TRPV2 channel. TRPV2 mRNA has been detected in CD4+ and CD8+ T cells as well as in human B lymphocytes. TRPV2 is one type of ion channel that directs T cell activation, proliferation, and defense mechanisms. If the TRPV2 channel were absent or not functioning properly in T cells, T cell receptor signaling would not be optimal. TRPV2 also acts as a transmembrane protein on the surface of B cells, negatively controlling B cell activation.[15] Abnormal TRPV2 expression has been reported in hematological diseases including multiple myeloma, myelodysplastic syndrome, Burkitt lymphoma, and acute myeloid leukemia.[14]
## Metabolic
TRPV2 seems to be essential in glucose homeostasis. It is highly expressed in MIN6 cells, which is a β-cell. These cell types are known for releasing insulin, a molecule that functions to keep glucose levels low. Under unstimulated conditions, TRPV2 is localized in the cytoplasm. Activation causes the channel to translocate to the plasma membrane. This triggers the influx of calcium resulting in insulin secretion.[3]
## Cardiovascular
TRPV2 is very important in the structure and function of cardiomyocytes (heart cells). Compared to skeletal muscles, TRPV2 is expressed 10 times as high in cardiomyocytes[17] and is important in current conduction. TRPV2 has been shown to be involved in stretch-dependent responses in heart cells. TRPV2 expression is concentrated in intercalated discs which allows the synchronous contraction of cardiomyocytes. Abnormal expression of TRPV2 results in reduced shortening length, shortening rate, and lengthening rate which ultimately compromise cardiac contractile function.
## Central nervous system
The cannabis constituent, cannabidiol (CBD), is a compound that acts in the release of neurotransmitters in the brain (part of the class of chemicals called cannabinoids) and has been researched for its positive effects in the treatment of epilepsy. CBD is able to bind to TRPV2 (as only plant-derived cannabinoids are TRPV2 agonists),[18] which results in a reduction of epileptic activity and, consequently, a decrease in mortality. Recent research demonstrated that, in vitro, CBD decreases epileptiform local field potential burst amplitude and burst duration and increases burst frequency. Testing CBD in vivo indicated a decrease in severe seizure incidence (an increase in anticonvulsant effects). Therefore, CBD increases the expression and activation of TRPV2, resulting in the inhibition of epileptic activity both in vitro and in vivo.[19] | https://www.wikidoc.org/index.php/TRPV2 | |
84fb92d9b219d8447630b5750ca59c8ad717d0bf | wikidoc | TRPV3 | TRPV3
Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.
The TRPV3 protein belongs to a family of nonselective cation channels that function in a variety of processes, including temperature sensation and vasoregulation. The thermosensitive members of this family are expressed in subsets of human sensory neurons that terminate in the skin, and are activated at distinct physiological temperatures. This channel is activated at temperatures between 22 and 40 degrees C. The gene lies in close proximity to another family member (TRPV1) gene on chromosome 17, and the two encoded proteins are thought to associate with each other to form heteromeric channels.
# Physiology of TRPV3 channel
The TRPV3 channel is widely expressed in the human body, especially in the skin in keratinocytes, but also in the brain. It functions as a molecular sensor for innocuous warm temperatures. Mice lacking these protein are unable to sense elevated temperatures (>33 °C) but are able to sense cold and noxious heat. In addition to thermosensation TRPV3 channels seem to play a role in hair growth because mutations in the TRPV3 gene cause hair loss in mice. The role of TRPV3 channels in the brain is unclear, but researchers found that they play a role in mood regulation, and that a protective effects of Incensole acetate were partially mediated by TRPV3 channels.
# Modulation
The TRPV3 channel is directly activated by various natural compounds like carvacrol, thymol and eugenol. Several other monoterpenoids which cause either feeling of warmth or are skin sensitizers can also open the channel. Monoterpenoids also induce agonist-specific desensitization of TRPV3 channels in a calcium-independent manner.
Resolvin E1 (RvE1), RvD2, and 17R-RvD1 (see resolvins) are metabolites of the omega 3 fatty acids, eicosapentaenoic acid (for RvE1) or docosahexaenoic acid (for RvD2 and 17R-RvD1). These metabolites are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV3, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on neruons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down-regulate TRPV3 and thereby pain perception. | TRPV3
Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.
The TRPV3 protein belongs to a family of nonselective cation channels that function in a variety of processes, including temperature sensation and vasoregulation. The thermosensitive members of this family are expressed in subsets of human sensory neurons that terminate in the skin, and are activated at distinct physiological temperatures. This channel is activated at temperatures between 22 and 40 degrees C. The gene lies in close proximity to another family member (TRPV1) gene on chromosome 17, and the two encoded proteins are thought to associate with each other to form heteromeric channels.[1]
# Physiology of TRPV3 channel
The TRPV3 channel is widely expressed in the human body, especially in the skin in keratinocytes, but also in the brain. It functions as a molecular sensor for innocuous warm temperatures.[2] Mice lacking these protein are unable to sense elevated temperatures (>33 °C) but are able to sense cold and noxious heat.[3] In addition to thermosensation TRPV3 channels seem to play a role in hair growth because mutations in the TRPV3 gene cause hair loss in mice.[4] The role of TRPV3 channels in the brain is unclear, but researchers found that they play a role in mood regulation,[5] and that a protective effects of Incensole acetate were partially mediated by TRPV3 channels.[6]
# Modulation
The TRPV3 channel is directly activated by various natural compounds like carvacrol, thymol and eugenol.[7] Several other monoterpenoids which cause either feeling of warmth or are skin sensitizers can also open the channel.[8] Monoterpenoids also induce agonist-specific desensitization of TRPV3 channels in a calcium-independent manner.[9]
Resolvin E1 (RvE1), RvD2, and 17R-RvD1 (see resolvins) are metabolites of the omega 3 fatty acids, eicosapentaenoic acid (for RvE1) or docosahexaenoic acid (for RvD2 and 17R-RvD1). These metabolites are members of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. These SPMs also dampen pain perception arising from various inflammation-based causes in animal models. The mechanism behind their pain-dampening effects involves the inhibition of TRPV3, probably (in at least certain cases) by an indirect effect wherein they activate other receptors located on neruons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which these SPMs operate to down-regulate TRPV3 and thereby pain perception.[10][11][12][13][14] | https://www.wikidoc.org/index.php/TRPV3 | |
6b4a79fa2727cd59bed370639b263b70cb88beaa | wikidoc | TRPV4 | TRPV4
Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.
The TRPV4 gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channel" (VR-OAC) and "OSM9-like transient receptor potential channel, member 4 (OTRPC4)", a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that has been found involved in multiple physiologic functions, dysfunctions and also disease. It functions in the regulation of systemic osmotic pressure by the brain, in vascular function, in liver, intestinal, renal and bladder function, in skin barrier function and response of the skin to ultraviolet-B radiation, in growth and structural integrity of the skeleton, in function of joints, in airway- and lung function, in retinal and inner ear function, and in pain. The channel is activated by osmotic, mechanical and chemical cues. It also responds to thermal changes (warmth). Channel activation can be sensitized by inflammation and injury.
The TRPV4 gene has been co-discovered by W. Liedtke et al. and R. Strotmann et al.
# Clinical significance
Channelopathy mutations in the TRPV4 gene lead to skeletal dysplasias, premature osteoarthritis, and neurological motor function disorders and are associated with a range of disorders, including brachyolmia type 3, congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy, and subtype 2C of Charcot–Marie–Tooth disease.
# Pharmacology
A number of TRPV4 agonists and antagonists have been identified since its discovery. The discovery of unselective modulators (e.g. antagonist Ruthenium Red) was followed by the apparition of more potent (agonist 4aPDD) or selective (antagonist RN-1734) compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047 (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893 (with ~50 fold selectivity vs TRPM8 and ~10 fold selectivity vs M1).
Resolvin D1 (RvD1), a metabolite of the omega 3 fatty acid, docosahexaenoic acid, is a member of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. This SPM also dampens pain perception arising from various inflammation-based causes in animal models. The mechanism behind this pain-dampening effect involves the inhibition of TRPV4, probably (in at least certain cases) by an indirect effect wherein it activates another receptor located on neruons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which a SPM may operate to down-regulate TRPs and thereby pain perception.
# Interactions
TRPV4 has been shown to interact with MAP7 and LYN. | TRPV4
Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.
The TRPV4 gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channel" (VR-OAC) and "OSM9-like transient receptor potential channel, member 4 (OTRPC4)",[1][2] a member of the vanilloid subfamily in the transient receptor potential (TRP) superfamily of ion channels.[3][4][5] The encoded protein is a Ca2+-permeable, nonselective cation channel that has been found involved in multiple physiologic functions, dysfunctions and also disease. It functions in the regulation of systemic osmotic pressure by the brain, in vascular function, in liver, intestinal, renal and bladder function, in skin barrier function and response of the skin to ultraviolet-B radiation, in growth and structural integrity of the skeleton, in function of joints, in airway- and lung function, in retinal and inner ear function, and in pain. The channel is activated by osmotic, mechanical and chemical cues. It also responds to thermal changes (warmth). Channel activation can be sensitized by inflammation and injury.
The TRPV4 gene has been co-discovered by W. Liedtke et al.[1] and R. Strotmann et al.[2]
# Clinical significance
Channelopathy mutations in the TRPV4 gene lead to skeletal dysplasias, premature osteoarthritis, and neurological motor function disorders and are associated with a range of disorders, including brachyolmia type 3, congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy, and subtype 2C of Charcot–Marie–Tooth disease.[6]
# Pharmacology
A number of TRPV4 agonists and antagonists have been identified since its discovery.[7] The discovery of unselective modulators (e.g. antagonist Ruthenium Red) was followed by the apparition of more potent (agonist 4aPDD)[8] or selective (antagonist RN-1734)[9] compounds, including some with bioavailability suitable for in vivo pharmacology studies such as agonist GSK1016790A[10] (with ~10 fold selectivity vs TRPV1), and antagonists HC-067047[11] (with ~5 fold selectivity vs hERG and ~10 fold selectivity vs TRPM8) and RN-9893[12] (with ~50 fold selectivity vs TRPM8 and ~10 fold selectivity vs M1).
Resolvin D1 (RvD1), a metabolite of the omega 3 fatty acid, docosahexaenoic acid, is a member of the specialized proresolving mediators (SPMs) class of metabolites that function to resolve diverse inflammatory reactions and diseases in animal models and, it is proposed, humans. This SPM also dampens pain perception arising from various inflammation-based causes in animal models. The mechanism behind this pain-dampening effect involves the inhibition of TRPV4, probably (in at least certain cases) by an indirect effect wherein it activates another receptor located on neruons or nearby microglia or astrocytes. CMKLR1, GPR32, FPR2, and NMDA receptors have been proposed to be the receptors through which a SPM may operate to down-regulate TRPs and thereby pain perception.[13][14][15][16][17]
# Interactions
TRPV4 has been shown to interact with MAP7[18] and LYN.[19] | https://www.wikidoc.org/index.php/TRPV4 | |
55e716a079aa2b176ee21842693e7b9254dcd2b5 | wikidoc | TRPV5 | TRPV5
Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.
TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the urine, and consequentual hyperparathyroidism, and bone loss.
# Function
This gene is a member of the transient receptor family and the TRPV subfamily. The calcium-selective channel, TRPV5, encoded by this gene has 6 transmembrane-spanning domains, multiple potential phosphorylation sites, an N-linked glycosylation site, and 5 ANK repeats. This protein forms homotetramers or heterotetramers and is activated by a low internal calcium level.
# Interactions
TRPV5 has been shown to interact with S100A10. | TRPV5
Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.[1][2][3]
TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.[4] Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the urine, and consequentual hyperparathyroidism, and bone loss.[5]
# Function
This gene is a member of the transient receptor family and the TRPV subfamily. The calcium-selective channel, TRPV5, encoded by this gene has 6 transmembrane-spanning domains, multiple potential phosphorylation sites, an N-linked glycosylation site, and 5 ANK repeats. This protein forms homotetramers or heterotetramers and is activated by a low internal calcium level.[6]
# Interactions
TRPV5 has been shown to interact with S100A10.[7] | https://www.wikidoc.org/index.php/TRPV5 | |
64bc34307729190010253fd09d8cfe1d8dc7434d | wikidoc | TRPV6 | TRPV6
TRPV6 is a membrane calcium channel which is particularly involved in the first step in calcium absorption in the intestine.
# Nomenclature
When first discovered it was named CAT1, or ECaC2. The name TRPV6 was confirmed in 2005.
TRPV6 is a member of the transient receptor potential (TRP) family of membrane proteins. Unlike most TRP channels, TRPV6 is selective for Ca2+ ions, a property shared with its close homologue, TRPV5, which is mainly expressed in the kidney and plays a role in renal Ca2+ reabsorption.
# Expression
TRPV6 expression has been described in the intestine in several species, including humans. The protein is located in the apical brush-border membrane of the intestinal enterocyte where it regulates calcium entry into the cell. It is most abundant in the proximal small intestine (duodenum and jejunum), along with the other calcium transport proteins, calbindin and the calcium-pumping ATPase, PMCA1. The TRPV6 calcium transporter also found in the human placenta, pancreas and prostate gland and in some species in the kidney, where the related channel TRPV5 is strongly expressed.
# Regulation of expression
## Vitamin D
Expression of TRPV6 is vitamin D dependent in mice and humans. Its expression was greatly reduced in animals that do not express the vitamin D receptor.
Vitamin D treatment of human colon cancer cells, Caco-2, increased expression of TRPV6 transcripts, and also stimulated the transport of calcium, probably through increased TRPV6 expression. In human duodenal explants, TRPV6 transcript expression was increased 3-fold after 6h incubation with the active form of vitamin D, 1,25-dihydroxycholecalciferol. | TRPV6
TRPV6 is a membrane calcium channel which is particularly involved in the first step in calcium absorption in the intestine.
# Nomenclature
When first discovered it was named CAT1,[1] or ECaC2.[2] The name TRPV6 was confirmed in 2005.[3]
TRPV6 is a member of the transient receptor potential (TRP) family of membrane proteins. Unlike most TRP channels, TRPV6 is selective for Ca2+ ions, a property shared with its close homologue, TRPV5, which is mainly expressed in the kidney and plays a role in renal Ca2+ reabsorption.[4]
# Expression
TRPV6 expression has been described in the intestine in several species, including humans.[5] The protein is located in the apical brush-border membrane of the intestinal enterocyte where it regulates calcium entry into the cell. It is most abundant in the proximal small intestine (duodenum and jejunum), along with the other calcium transport proteins, calbindin and the calcium-pumping ATPase, PMCA1. The TRPV6 calcium transporter also found in the human placenta, pancreas and prostate gland and in some species in the kidney, where the related channel TRPV5 is strongly expressed.
# Regulation of expression
## Vitamin D
Expression of TRPV6 is vitamin D dependent in mice and humans. Its expression was greatly reduced in animals that do not express the vitamin D receptor.[6]
Vitamin D treatment of human colon cancer cells, Caco-2, increased expression of TRPV6 transcripts, and also stimulated the transport of calcium, probably through increased TRPV6 expression.[7] In human duodenal explants, TRPV6 transcript expression was increased 3-fold after 6h incubation with the active form of vitamin D, 1,25-dihydroxycholecalciferol.[8] | https://www.wikidoc.org/index.php/TRPV6 | |
c2cb1db7523b18107735e996a927cc69bb37f6a0 | wikidoc | TSG-6 | TSG-6
Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein that in humans is encoded by the TNFAIP6 (tumor necrosis factor, alpha-induced protein 6) gene.
# Structure and function
TSG-6 is a 30 kDa secreted protein that contains a hyaluronan-binding LINK domain a and thus is a member of the hyaluronan-binding protein family, also called hyaladherins. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. This protein has been shown to form a stable, covalent complex with inter-alpha-inhibitor (IαI), and thus enhance the serine protease inhibitory activity of IαI, which is important in the protease network associated with inflammation. The expression of this gene can be induced by a number of signalling molecules, principally tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The expression can also be induced by mechanical stimuli in vascular smooth muscle cells, and is found to be correlated with proteoglycan synthesis and aggregation. TSG-6 has been shown to modulate macrophage plasticity and signal the transition of LPS-treated macrophages from pro- to anti-inflammatory phenotype.
TSG-6 also interacts with a number of matrix associated molecules such as aggrecan, versican, thrombospondin (1&2), pentraxin-3 and fibronectin. | TSG-6
Tumor necrosis factor-inducible gene 6 protein also known as TNF-stimulated gene 6 protein or TSG-6 is a protein[1] that in humans is encoded by the TNFAIP6 (tumor necrosis factor, alpha-induced protein 6) gene.[2][3]
# Structure and function
TSG-6 is a 30 kDa secreted protein that contains a hyaluronan-binding LINK domain a and thus is a member of the hyaluronan-binding protein family, also called hyaladherins. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. This protein has been shown to form a stable, covalent complex with inter-alpha-inhibitor (IαI), and thus enhance the serine protease inhibitory activity of IαI, which is important in the protease network associated with inflammation. The expression of this gene can be induced by a number of signalling molecules, principally tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The expression can also be induced by mechanical stimuli in vascular smooth muscle cells, and is found to be correlated with proteoglycan synthesis and aggregation.[3] TSG-6 has been shown to modulate macrophage plasticity and signal the transition of LPS-treated macrophages from pro- to anti-inflammatory phenotype.[4]
TSG-6 also interacts with a number of matrix associated molecules such as aggrecan, versican, thrombospondin (1&2), pentraxin-3 and fibronectin. | https://www.wikidoc.org/index.php/TSG-6 | |
17865ea4d7017b194ffc9b5554e6cb924e4d39ed | wikidoc | TSHZ3 | TSHZ3
Teashirt homolog 3 is a protein that in humans is encoded by the TSHZ3 gene. In mice, it is a necessary part of the neural circuitry that controls breathing. The gene is also a homolog of the Drosophila melanogaster teashirt gene, which encodes a zinc finger transcription factor important for development of the trunk.
Tshz3-knockout mice do not develop the respiratory rhythm generator (RRG) neural circuit, which is a pacemaker that produces an oscillating rhythm in the brainstem and controls autonomous breathing. The RRG neurons are present, but are abnormal. Those mice do not survive because they don't initiate breathing after birth. Tshz3 is being studied for its relationship to infant breathing defects in humans.
TSHZ3 has been identified as a critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD) symptoms such autistic traits, speech disturbance and intellectual disability, as well as renal tract abnormalities. Mice with heterozygous Tshz3 deletion (Tshz3lacZ/+) show enrichment of ASD-related gene orthologs in the cerebral cortex, functional alterations of corticostriatal circuitry and ASD-relevant behavioral abnormalities. | TSHZ3
Teashirt homolog 3 is a protein that in humans is encoded by the TSHZ3 gene.[1] In mice, it is a necessary part of the neural circuitry that controls breathing. The gene is also a homolog of the Drosophila melanogaster teashirt gene, which encodes a zinc finger transcription factor important for development of the trunk.
Tshz3-knockout mice do not develop the respiratory rhythm generator (RRG) neural circuit, which is a pacemaker that produces an oscillating rhythm in the brainstem and controls autonomous breathing. The RRG neurons are present, but are abnormal. Those mice do not survive because they don't initiate breathing after birth. Tshz3 is being studied for its relationship to infant breathing defects in humans.[2]
TSHZ3 has been identified as a critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD) symptoms such autistic traits, speech disturbance and intellectual disability, as well as renal tract abnormalities. Mice with heterozygous Tshz3 deletion (Tshz3lacZ/+) show enrichment of ASD-related gene orthologs in the cerebral cortex, functional alterations of corticostriatal circuitry and ASD-relevant behavioral abnormalities.
[3] | https://www.wikidoc.org/index.php/TSHZ3 | |
b475fae10c009838c96b774301b1bede5a219e37 | wikidoc | TTC19 | TTC19
Tetratricopeptide repeat domain 19, also known as TPR repeat protein 19 or Tetratricopeptide repeat protein 19, mitochondrial is a protein that in humans is encoded by the TTC19 gene. This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 amino acids each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene.
# Structure
The TTC19 gene is located on the p arm of chromosome 17 at position 12 and it spans 46,048 base pairs. The TTC19 gene produces a 16 kDa protein composed of 149 amino acids. TTC19 is a subunit of the enzyme Ubiquinol Cytochrome c Reductase (UQCR, Complex III or Cytochrome bc1 complex) of the mitochondrial respiratory chain, which consists of the products of one mitochondrially encoded gene, MTCYTB (mitochondrial cytochrome b) and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1 (Rieske protein), UQCRB, "14kDa protein", UQCRH (cyt c1 Hinge protein), Rieske Protein presequence, "cyt. c1 associated protein", and "Rieske-associated protein". The structure of the complex is a symmetric homodimer composed of one mitochondrial genome encoded cytochrome b subunit and ten other nucleus encoded subunits.
# Function
The TTC19 gene encodes for one of the ten nuclear proteins essential for the assembly and function of the Ubiquinol Cytochrome c Reductase or Complex III of the mitochondrial respiratory chain. The Ubiquinol Cytochrome c Reductase is responsible for catalyzing the transfer of electrons from coenzyme Q to cytochrome c as well as pumping protons from the matrix into the inner membrane which results in the generation of an ATP-coupled electrochemical potential. The TTC19 subunit is necessary for the preservation of the structural and functional integrity of Ubiquinol Cytochrome c Reductase, which is achieved by allowance of the physiological turnover of the Rieske protein (UQCRFS1). It also participates in the clearance of UQCRFS1 N-terminal fragments which are produced by the addition of UQCRFS1 into the Ubiquinol Cytochrome c Reductase and whose presence may lead to the failure of the complex's catalytic activity.
# Clinical significance
Variants of TTC19 have been associated with mitochondrial complex III deficiency, nuclear 2 (MC3DN2). TTC19 is known to cause this deficiency through the failed assembly of the Ubiquinol Cytochrome c Reductase. Mitochondrial complex III deficiency, nuclear (type 2) is a diverse group of neuromuscular and multi-systemic disorders caused by a dysfunction of the mitochondrial respiratory chain which may result in highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance. In addition, mutations in TTC19 is also known to be associated with various neurological disorders in both childhood and adulthood.
All Pathogenic mutations of this gene have been reported to be nonsense mutations. Such mutations have included (c.937C>T; p. Q313X), (c.157_158dup), and (c.829C > T; p.Q277*).
# Interactions
TTC19 binds to the mature mitochondrial complex III dimer after the incorporation of the Rieske protein UQCRFS1. Additional interactions include interactions with proteins UQCRC1, UQCRFS1 (by similarity), ZFYVE26, and CHMP4B. | TTC19
Tetratricopeptide repeat domain 19, also known as TPR repeat protein 19 or Tetratricopeptide repeat protein 19, mitochondrial is a protein that in humans is encoded by the TTC19 gene. This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 amino acids each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene.[1]
# Structure
The TTC19 gene is located on the p arm of chromosome 17 at position 12 and it spans 46,048 base pairs.[1] The TTC19 gene produces a 16 kDa protein composed of 149 amino acids.[2][3] TTC19 is a subunit of the enzyme Ubiquinol Cytochrome c Reductase (UQCR, Complex III or Cytochrome bc1 complex) of the mitochondrial respiratory chain, which consists of the products of one mitochondrially encoded gene, MTCYTB (mitochondrial cytochrome b) and ten nuclear genes: UQCRC1, UQCRC2, Cytochrome c1, UQCRFS1 (Rieske protein), UQCRB, "14kDa protein", UQCRH (cyt c1 Hinge protein), Rieske Protein presequence, "cyt. c1 associated protein", and "Rieske-associated protein".[1] The structure of the complex is a symmetric homodimer composed of one mitochondrial genome encoded cytochrome b subunit and ten other nucleus encoded subunits.[4]
# Function
The TTC19 gene encodes for one of the ten nuclear proteins essential for the assembly and function of the Ubiquinol Cytochrome c Reductase or Complex III of the mitochondrial respiratory chain. The Ubiquinol Cytochrome c Reductase is responsible for catalyzing the transfer of electrons from coenzyme Q to cytochrome c as well as pumping protons from the matrix into the inner membrane which results in the generation of an ATP-coupled electrochemical potential. The TTC19 subunit is necessary for the preservation of the structural and functional integrity of Ubiquinol Cytochrome c Reductase, which is achieved by allowance of the physiological turnover of the Rieske protein (UQCRFS1).[5][6][7][8] It also participates in the clearance of UQCRFS1 N-terminal fragments which are produced by the addition of UQCRFS1 into the Ubiquinol Cytochrome c Reductase and whose presence may lead to the failure of the complex's catalytic activity.[5][6][7]
# Clinical significance
Variants of TTC19 have been associated with mitochondrial complex III deficiency, nuclear 2 (MC3DN2). TTC19 is known to cause this deficiency through the failed assembly of the Ubiquinol Cytochrome c Reductase.[9] Mitochondrial complex III deficiency, nuclear (type 2) is a diverse group of neuromuscular and multi-systemic disorders caused by a dysfunction of the mitochondrial respiratory chain which may result in highly variable phenotype depending on which tissues are affected. Clinical features include mitochondrial encephalopathy, psychomotor retardation, ataxia, severe failure to thrive, liver dysfunction, renal tubulopathy, muscle weakness and exercise intolerance.[6][7][8] In addition, mutations in TTC19 is also known to be associated with various neurological disorders in both childhood and adulthood.
All Pathogenic mutations of this gene have been reported to be nonsense mutations. Such mutations have included (c.937C>T; p. Q313X), (c.157_158dup), and (c.829C > T; p.Q277*).[10][11][12]
# Interactions
TTC19 binds to the mature mitochondrial complex III dimer after the incorporation of the Rieske protein UQCRFS1. Additional interactions include interactions with proteins UQCRC1, UQCRFS1 (by similarity), ZFYVE26, and CHMP4B.[6][7] | https://www.wikidoc.org/index.php/TTC19 | |
77d0abfc0251753e5dd9c2b384e411b1eafedac3 | wikidoc | TTC7A | TTC7A
Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.
# Function
TPR domain-containing proteins, such as TTC7A, have diverse functions in cell cycle control, protein transport, phosphate turnover, and protein trafficking or secretion, and they can act as chaperones or scaffolding proteins.
# Clinical significance
TTC7A deficiency is extremely rare with less than 30 cases reported to date. TTC7A deficiency disrupts epithelial intestinal cell growth thereby promoting multiple intestinal atresia (MIA), a rare type of bowel obstruction. Not all patients with TTC7A Deficiency exhibit the same symptoms. Although quality of life is generally very poor for most children with very few surviving beyond the first year or two of life, there is a broad spectrum of severity of symptoms varying from individual to individual with some forms of TTC7A Deficiency being less severe with survival being many years or even decades.
Mutations in this gene are known to cause hereditary multiple intestinal atresia (MIA), severe infantile or very early onset inflammatory bowel disease, extensive enteropathy, combined immunodeficiencies (CID), thyroid dysfunction, and alopecia. Some TTC7A Deficiency patients have also been shown to develop lung disease
There is no standard treatment for TTC7A Deficiency at this time. Management of TTC7A deficiency currently entails bowel resection for any atresias, possibly hematopoietic stem cell transplantation to correct the immunodeficiencies, and immunosuppression to help alleviate bowel disease and immune disregulation. Hematopoietic stem cell transplantation may be ineffective.Small bowel transplant has proven successful in at least one case.
## Effect on Rho kinase activity
Research indicates that TTC7A deficiency results in "increased Rho kinase activity which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development." Based on this research, it has been proposed that Rho kinase inhibitors may be a therapeutic option, although no specific rho kinase inhibitors are currently available for patient use with the exception of Fasudil which is only available in Japan.
It has been shown that statins such as Lipitor are useful as Rho kinase inhibitors. Therefore, statins may be helpful for the treatment of TTC7A deficiency, although this has yet to be proven. | TTC7A
Tetratricopeptide repeat domain 7A (TTC7A) is a protein that in humans is encoded by the TTC7A gene.[1]
# Function
TPR domain-containing proteins, such as TTC7A, have diverse functions in cell cycle control, protein transport, phosphate turnover, and protein trafficking or secretion, and they can act as chaperones or scaffolding proteins.
# Clinical significance
TTC7A deficiency is extremely rare with less than 30 cases reported to date.[citation needed] TTC7A deficiency disrupts epithelial intestinal cell growth thereby promoting multiple intestinal atresia (MIA), a rare type of bowel obstruction.[2] Not all patients with TTC7A Deficiency exhibit the same symptoms. Although quality of life is generally very poor for most children with very few surviving beyond the first year or two of life,[3] there is a broad spectrum of severity of symptoms varying from individual to individual with some forms of TTC7A Deficiency being less severe with survival being many years or even decades.
Mutations in this gene are known to cause hereditary multiple intestinal atresia (MIA), severe infantile or very early onset inflammatory bowel disease, extensive enteropathy, combined immunodeficiencies (CID), thyroid dysfunction, and alopecia.[4][5][6][7] Some TTC7A Deficiency patients have also been shown to develop lung disease [8][9][10]
There is no standard treatment for TTC7A Deficiency at this time. Management of TTC7A deficiency currently entails bowel resection for any atresias, possibly hematopoietic stem cell transplantation to correct the immunodeficiencies, and immunosuppression to help alleviate bowel disease and immune disregulation. Hematopoietic stem cell transplantation may be ineffective.[11]Small bowel transplant has proven successful in at least one case.[12]
## Effect on Rho kinase activity
Research indicates that TTC7A deficiency results in "increased Rho kinase activity which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development." [13] Based on this research, it has been proposed that Rho kinase inhibitors may be a therapeutic option, although no specific rho kinase inhibitors are currently available for patient use with the exception of Fasudil which is only available in Japan.
It has been shown that statins such as Lipitor are useful as Rho kinase inhibitors.[14] Therefore, statins may be helpful for the treatment of TTC7A deficiency, although this has yet to be proven. | https://www.wikidoc.org/index.php/TTC7A | |
a6c5e32ca9873e8109114590c06e1931950774b4 | wikidoc | TTLL3 | TTLL3
Tubulin tyrosine ligase-like family, member 3 is a protein that in humans is encoded by the TTLL3 gene.
# Model organisms
Model organisms have been used in the study of TTLL3 function. A conditional knockout mouse line, called Ttll3tm1a(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 on mutant mice but no significant abnormalities were observed. | TTLL3
Tubulin tyrosine ligase-like family, member 3 is a protein that in humans is encoded by the TTLL3 gene.[1]
# Model organisms
Model organisms have been used in the study of TTLL3 function. A conditional knockout mouse line, called Ttll3tm1a(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 — at the Wellcome Trust Sanger Institute.[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 but no significant abnormalities were observed.[4] | https://www.wikidoc.org/index.php/TTLL3 | |
f4542a17317a3439c61951c641a0b0205fe1f273 | wikidoc | TTRAP | TTRAP
TRAF and TNF receptor-associated protein is a protein that in humans is encoded by the TTRAP gene.
# Function
This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors.
# Interactions
TTRAP has been shown to interact with ETS1, TNFRSF1B and CD40. | TTRAP
TRAF and TNF receptor-associated protein is a protein that in humans is encoded by the TTRAP gene.[1][2]
# Function
This gene encodes a member of a superfamily of divalent cation-dependent phosphodiesterases. The encoded protein associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor associated factors (TRAFs), and inhibits nuclear factor-kappa-B activation. This protein has sequence and structural similarities with APE1 endonuclease, which is involved in both DNA repair and the activation of transcription factors.[2]
# Interactions
TTRAP has been shown to interact with ETS1,[3] TNFRSF1B[4] and CD40.[4] | https://www.wikidoc.org/index.php/TTRAP | |
4cf537e28d90b4e093253d394601475e3c54f1aa | wikidoc | TYRP1 | TYRP1
Tyrosinase-related protein 1, also known as TYRP1, is an enzyme which in humans is encoded by the TYRP1 gene.
# Function
Tyrp1 is a melanocyte-specific gene product involved in melanin synthesis. While mouse Tyrp1 possesses dihydroxyindole carboxylic acid oxidase activity, the function in human melanocytes is less clear. In addition to its role in melanin synthesis, Tyrp1 is involved in stabilizing of tyrosinase protein and modulating its catalytic activity. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and melanocyte cell death.
# Clinical significance
Mutations in the mouse Tyrp1 gene are associated with brown pelage and in the human TYRP1 gene with oculocutaneous albinism type 3 (OCA3). An allele of TYRP1 common in Solomon Islanders results in blond hair. Although the phenotype is similar to Northern European blond hair, this allele is not found in Europeans.
# Regulation
The expression of TYRP1 is regulated by the microphthalmia-associated transcription factor (MITF).
# Interactions
TYRP1 has been shown to interact with GIPC1. | TYRP1
Tyrosinase-related protein 1, also known as TYRP1, is an enzyme which in humans is encoded by the TYRP1 gene.[1][2]
# Function
Tyrp1 is a melanocyte-specific gene product involved in melanin synthesis. While mouse Tyrp1 possesses dihydroxyindole carboxylic acid oxidase activity, the function in human melanocytes is less clear. In addition to its role in melanin synthesis, Tyrp1 is involved in stabilizing of tyrosinase protein and modulating its catalytic activity. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and melanocyte cell death.[3]
# Clinical significance
Mutations in the mouse Tyrp1 gene are associated with brown pelage and in the human TYRP1 gene with oculocutaneous albinism type 3 (OCA3).[3] An allele of TYRP1 common in Solomon Islanders results in blond hair. Although the phenotype is similar to Northern European blond hair, this allele is not found in Europeans.[4][5]
# Regulation
The expression of TYRP1 is regulated by the microphthalmia-associated transcription factor (MITF).[6][7]
# Interactions
TYRP1 has been shown to interact with GIPC1.[8] | https://www.wikidoc.org/index.php/TYRP1 | |
93cbd4857543913c97f580435a933bdf2571e907 | wikidoc | Tansy | Tansy
Tansy (Tanacetum vulgare) is a perennial herbaceous flowering plant of the aster family that is native to temperate Europe and Asia. It has been introduced to other parts of the world and in some cases has become invasive. It is also known as Common Tansy, Bitter Buttons, Cow Bitter, Mugwort, or Golden Buttons.
# Description
Tansy is a flowering herb with finely divided compound leaves and yellow, buttonlike flowers. It has a stout, somewhat reddish, erect stem, usually smooth, 50-150 cm tall, and branching near the top. The leaves are alternate, 10-15 cm long and are pinnately lobed, divided almost to the center into about seven pairs of segments or lobes which are again divided into smaller lobes having saw-toothed edges, thus giving the leaf a somewhat fernlike appearance. The roundish, flat-topped, buttonlike, yellow flower heads are produced in terminal clusters from mid to late summer. The scent is similar to that of camphor with hints of rosemary. The leaves and flowers are said to be poisonous if consumed in large quantities. The plant's volatile oil is high in thujone, a substance found in absinthe that can cause convulsions. Some insects, notably the tansy beetle, have evolved resistance to tansy and live almost exclusively on it.
# History and distribution
Tansy is native to Eurasia; it is found in almost all parts of mainland Europe. It is absent from Siberia and some of the Mediterranean islands. The ancient Greeks may have been the first to cultivate it as a medicinal herb. In about 1525, it was listed (by the spelling "Tansey") as "necessary for a garden" in Britain.
# Culinary uses
Tansy was formerly used as a flavoring for puddings and omelets, but is almost unknown now. It was certainly relished in days gone by, for Gerarde speaks of them as "pleasant in taste", and he recommends tansy sweetmeats as "an especial thing against the gout, if every day for a certain space a reasonable quantitie thereof be eaten fasting". In Yorkshire, tansy and caraway seeds were traditionally used in biscuits served at funerals. According to liquor historian A. J. Baime's book Big Shots, Tennessee whiskey magnate Jack Daniel enjoyed drinking his own whiskey with sugar and crushed tansy leaf.
# Ethnomedical use
For many years, tansy has been used as a medicinal herb. Irish folklore of the mid-1800s suggests bathing in a solution of tansy and salt as a cure for joint pain. Bitter tea made with the blossoms of T. vulgare has been effectively used for centuries as an anthelmintic (vermifuge). Tansy cakes were traditionally served during Lent because of a superstition that eating fish during Lent caused intestinal worms. Note that only T. vulgare is used in medicinal preparations; all species of tansy are toxic, and an overdose can be fatal. The dried flowering herb of Tanacetum is used ethnomedically to treat migraine, neuralgia, and rheumatism, and as an antihelminthic, in conjunction with a competent herbalist to circumvent any possible toxicity. Formerly, tansy was often used for its emmenagogue effects, but rumors have implicated tansy in cases of miscarriage. Pregnant women should avoid this herb.
# Other uses
In England, bunches of tansy were traditionally placed at windows to keep out flies. Sprigs were placed in bedding and linen to drive away pests.
Tansy is used by some traditional dyers to produce a golden-yellow pigment. The yellow flowers are dried for use in floral arrangements.
Tansy is also used as a companion plant, especially with cucurbits like cucumbers and squash, or with roses or various berries. It is thought to repel ants, cucumber beetles, japanese beetles, squash bugs, and some kinds of flying insects, among others.
# Tansy in art and literature
A portion of a nineteenth-century poem by John Clare describes the delight of tansy and other herbs:
And where the marjoram once, and sage, and rue,
And balm, and mint, with curl'd-leaf parsley grew,
And double marigolds, and silver thyme,
And pumpkins 'neath the window climb;
And where I often, when a child, for hours
Tried through the pales to get the tempting flowers,
As lady's laces, everlasting peas,
True-love-lies-bleeding, with the hearts-at-ease,
And golden rods, and tansy running high,
That o'er the pale-tops smiled on passers-by.
From "The Cross Roads; or, The Haymaker's Story", available from a collection at Project Gutenberg. | Tansy
Tansy (Tanacetum vulgare) is a perennial herbaceous flowering plant of the aster family that is native to temperate Europe and Asia. It has been introduced to other parts of the world and in some cases has become invasive. It is also known as Common Tansy, Bitter Buttons, Cow Bitter, Mugwort, or Golden Buttons.
# Description
Tansy is a flowering herb with finely divided compound leaves and yellow, buttonlike flowers. It has a stout, somewhat reddish, erect stem, usually smooth, 50-150 cm tall, and branching near the top. The leaves are alternate, 10-15 cm long and are pinnately lobed, divided almost to the center into about seven pairs of segments or lobes which are again divided into smaller lobes having saw-toothed edges, thus giving the leaf a somewhat fernlike appearance. The roundish, flat-topped, buttonlike, yellow flower heads are produced in terminal clusters from mid to late summer. The scent is similar to that of camphor with hints of rosemary. The leaves and flowers are said to be poisonous if consumed in large quantities. The plant's volatile oil is high in thujone, a substance found in absinthe that can cause convulsions. Some insects, notably the tansy beetle, have evolved resistance to tansy and live almost exclusively on it.
# History and distribution
Tansy is native to Eurasia; it is found in almost all parts of mainland Europe. It is absent from Siberia and some of the Mediterranean islands.[1] The ancient Greeks may have been the first to cultivate it as a medicinal herb.[2] In about 1525, it was listed (by the spelling "Tansey") as "necessary for a garden" in Britain.[3]
# Culinary uses
Tansy was formerly used as a flavoring for puddings and omelets, but is almost unknown now. It was certainly relished in days gone by, for Gerarde speaks of them as "pleasant in taste", and he recommends tansy sweetmeats as "an especial thing against the gout, if every day for a certain space a reasonable quantitie thereof be eaten fasting". In Yorkshire, tansy and caraway seeds were traditionally used in biscuits served at funerals.[4] According to liquor historian A. J. Baime's book Big Shots, Tennessee whiskey magnate Jack Daniel enjoyed drinking his own whiskey with sugar and crushed tansy leaf.
# Ethnomedical use
For many years, tansy has been used as a medicinal herb. Irish folklore of the mid-1800s suggests bathing in a solution of tansy and salt as a cure for joint pain.[5] Bitter tea made with the blossoms of T. vulgare has been effectively used for centuries as an anthelmintic (vermifuge). Tansy cakes were traditionally served during Lent because of a superstition that eating fish during Lent caused intestinal worms.[4] Note that only T. vulgare is used in medicinal preparations; all species of tansy are toxic, and an overdose can be fatal. The dried flowering herb of Tanacetum is used ethnomedically to treat migraine, neuralgia, and rheumatism, and as an antihelminthic, in conjunction with a competent herbalist to circumvent any possible toxicity. Formerly, tansy was often used for its emmenagogue effects, but rumors have implicated tansy in cases of miscarriage. Pregnant women should avoid this herb. [6]
# Other uses
In England, bunches of tansy were traditionally placed at windows to keep out flies. Sprigs were placed in bedding and linen to drive away pests. [7]
Tansy is used by some traditional dyers to produce a golden-yellow pigment.[8] The yellow flowers are dried for use in floral arrangements.
Tansy is also used as a companion plant, especially with cucurbits like cucumbers and squash, or with roses or various berries. It is thought to repel ants, cucumber beetles, japanese beetles, squash bugs, and some kinds of flying insects, among others.
# Tansy in art and literature
A portion of a nineteenth-century poem by John Clare describes the delight of tansy and other herbs:
And where the marjoram once, and sage, and rue,
And balm, and mint, with curl'd-leaf parsley grew,
And double marigolds, and silver thyme,
And pumpkins 'neath the window climb;
And where I often, when a child, for hours
Tried through the pales to get the tempting flowers,
As lady's laces, everlasting peas,
True-love-lies-bleeding, with the hearts-at-ease,
And golden rods, and tansy running high,
That o'er the pale-tops smiled on passers-by.
From "The Cross Roads; or, The Haymaker's Story", available from a collection at Project Gutenberg. | https://www.wikidoc.org/index.php/Tansy | |
695bba18a364f096123fbc078c3fc9ebdba62663 | wikidoc | Taxon | Taxon
A taxon (plural taxa), or taxonomic unit, is a name designating an organism or group of organisms. In biological nomenclature according to Carl Linnaeus, a taxon is assigned a taxonomic rank and can be placed at a particular level in a systematic hierarchy reflecting evolutionary relationships.
A distinction is to be made between taxa/taxonomy and classification/systematics. The former refers to biological names and the rules of naming. The latter refers to rank ordering of taxa according to presumptive evolutionary (phylogenetic) relationships.
Note: "Phylum" applies formally to any biological domain, but traditionally it was always used for animals, whereas "Division" was traditionally often used for plants, fungi, etc.
A simple mnemonic phrase to remember the sequence of taxonomic levels is:
"Dignified Kings Play Chess On Fine Green Silk"; another, highly expedient example is "King Philip's Class Orders the Family Genius to Speak".
A prefix is used to indicate a ranking of lesser importance. The prefix super- indicates a rank above, the prefix sub- indicates a rank below. In zoology the prefix infra- indicates a rank below sub-. For instance:
Rank is relative, and restricted to a particular systematic schema. For example, liverworts have been grouped, in various systems of classification, as a family, order, class, or division (phylum). The use of a narrow set of ranks is challenged by users of cladistics; for example, the mere 10 ranks traditionally used between animal families (governed by the ICZN) and animal phyla (usually the highest relevant rank in taxonomic work) often cannot adequately represent the evolutionary history as more about a lineage's phylogeny becomes known. In addition, the class rank is quite often not an evolutionary but a phenetical and paraphyletic group and as opposed to those ranks governed by the ICZN, can usually not be made monophyletic by exchanging the taxa contained therein. This has given rise to phylogenetic taxonomy and the ongoing development of the PhyloCode, which is to govern the application of taxa to clades. | Taxon
Template:Biological classification
A taxon (plural taxa), or taxonomic unit, is a name designating an organism or group of organisms. In biological nomenclature according to Carl Linnaeus, a taxon is assigned a taxonomic rank and can be placed at a particular level in a systematic hierarchy reflecting evolutionary relationships.
A distinction is to be made between taxa/taxonomy and classification/systematics. The former refers to biological names and the rules of naming. The latter refers to rank ordering of taxa according to presumptive evolutionary (phylogenetic) relationships.
Note: "Phylum" applies formally to any biological domain, but traditionally it was always used for animals, whereas "Division" was traditionally often used for plants, fungi, etc.
A simple mnemonic phrase to remember the sequence of taxonomic levels is:
"Dignified Kings Play Chess On Fine Green Silk"; another, highly expedient example is "King Philip's Class Orders the Family Genius to Speak".
A prefix is used to indicate a ranking of lesser importance. The prefix super- indicates a rank above, the prefix sub- indicates a rank below. In zoology the prefix infra- indicates a rank below sub-. For instance:
Rank is relative, and restricted to a particular systematic schema. For example, liverworts have been grouped, in various systems of classification, as a family, order, class, or division (phylum). The use of a narrow set of ranks is challenged by users of cladistics; for example, the mere 10 ranks traditionally used between animal families (governed by the ICZN) and animal phyla (usually the highest relevant rank in taxonomic work) often cannot adequately represent the evolutionary history as more about a lineage's phylogeny becomes known. In addition, the class rank is quite often not an evolutionary but a phenetical and paraphyletic group and as opposed to those ranks governed by the ICZN, can usually not be made monophyletic by exchanging the taxa contained therein. This has given rise to phylogenetic taxonomy and the ongoing development of the PhyloCode, which is to govern the application of taxa to clades. | https://www.wikidoc.org/index.php/Taxa | |
bc2d7d174bb04ad83a7eb5dcb08c6d03348314c1 | wikidoc | Teeth | Teeth
Teeth are found in the mouths of humans and many other animals. The word teeth is the plural of the word tooth. Teeth are of various shapes, sizes and lengths.
Normally adult humans have 32 teeth in their mouth which help chew food.
Teeth have a natural coating which is called enamel.
Necessary care needs be excercised while cleaning or brushing them. Teeth in good condition have aesthetic appeal that attracts and pleases viewers.
# Theoretical teeth
Def. a "hard, calcareous structure present in the mouth of many vertebrate animals, generally used for eating" is called a tooth.
The pattern of incisors, canines, premolars and molars is found only in mammals, and to varying extents, in their evolutionary ancestors, but the numbers of these types of teeth vary greatly between species; zoologists use a standardised dental formula to describe the precise pattern in any given group.
The image on the right is a model of a human molar-like tooth. Its components are labeled:
- Tooth:
- Enamel
- Dentin
- Dental pulp:
- cameral pulp
- root pulp
- Cementum
- Crown
- Cusp
- Sulcus
- Cementoenamel junction or Neck
- Root
- Furcation
- Root apex
- Apical foramen
- Gingival sulcus
- Periodontium:
- Gingiva:
- free or interdental
- marginal
- alveolar
- Periodontal ligament
- Alveolar bone
- Vessels and nerves:
- dental
- periodontal
- alveolar through alveolar canals.
# Visuals
Teeth of humans are small, calcified, hard, whitish structures found in the mouth. They function in mechanically breaking down items of food by cutting and crushing them in preparation for swallowing and digestion. The roots of teeth are embedded in the maxilla (upper jaw) or the mandible (lower jaw) and are covered by gingiva or gums. Teeth are made of multiple tissues of varying density and hardness.
# Cetaceans
Like human teeth, whale teeth have polyp-like protrusions located on the root surface of the tooth are made of cementum in both animals, but in human teeth, the protrusions are located on the outside of the root, while in whales the nodule is located on the inside of the pulp chamber, with the roots of human teeth made of cementum on the outer surface, whales have cementum on the entire surface of the tooth with a very small layer of enamel at the tip only seen in older whales where the cementum has been worn away to show the underlying enamel.
# Mammuthus primigenius
On the right is an image of a molar tooth from a specimen (No. 201669, ELM G319:2) of the woolly mammoth Mammuthus primigenius. The tooth was collected about January 17, 2006, near Puurmani, Estonia, from a Quaternary deposit and the record for the tooth inserted into the collection on October 18, 2008.
The image on the right is of a lophodont cheek molar.
# Sahelanthropus tchadensis
"Sahelanthropus tchadensis is one of the oldest known species in the human family tree. This species lived sometime between 7 and 6 million years ago in West-Central Africa (Chad). Walking upright may have helped this species survive in diverse habitats, including forests and grasslands. Although we have only cranial material from Sahelanthropus, studies so far show this species had a combination of ape-like and human-like features. Ape-like features included a small brain (even slightly smaller than a chimpanzee’s), sloping face, very prominent browridges, and elongated skull. Human-like features included small canine teeth, a short middle part of the face, and a spinal cord opening underneath the skull instead of towards the back as seen in non-bipedal apes."
"Some of the oldest evidence of a humanlike species moving about in an upright position comes from Sahelanthropus. The foramen magnum (the large opening where the spinal cord exits out of the cranium from the brain) is located further forward (on the underside of the cranium) than in apes or any other primate except humans. This feature indicates that the head of Sahelanthropus was held on an upright body, probably associated with walking on two legs."
"The first (and, so far, only) fossils of Sahelanthropus are nine cranial specimens from northern Chad. A research team of scientists led by French paleontologist Michael Brunet uncovered the fossils in 2001, including the type specimen TM 266-1-606-1. Before 2001, early humans in Africa had only been found in the Great Rift Valley in East Africa and sites in South Africa, so the discovery of Sahelanthropus fossils in West-Central Africa shows that the earliest humans were more widely distributed than previously thought."
# Orrorin tugenensis
"Living around 6 million years ago, Orrorin tugenensis is the one of the oldest early humans on our family tree. Individuals of this species were approximately the size of a chimpanzee and had small teeth with thick enamel, similar to modern humans. The most important fossil of this species is an upper femur, showing evidence of bone buildup typical of a biped - so Orrorin tugenensis individuals climbed trees but also probably walked upright with two legs on the ground."
"A research team led by French paleontologist Brigitte Senut and French geologist Martin Pickford discovered this species in the Tugen Hills region of central Kenya. They found more than a dozen early human fossils dating between about 6.2 million and 6.0 million years old. Because of its novel combination of ape and human traits, the researchers gave a new genus and species name to these fossils, Orrorin tugenensis, which in the local language means “original man in the Tugen region.” So far, Orrorin tugenensis is the only species in the genus Orrorin."
"Orrorin’s femur (thigh bone) and humerus (upper arm bone) are about 1.5 times larger than those of Lucy’s (AL 288-1). Therefore, scientists estimate that Orrorin would have been 1.5 times larger than Au. afarensis, suggesting a size similar to a female chimpanzee, between about 30 and 50 kg."
# Horse
An adult horse has between 36 and 44 teeth, where the enamel and dentin layers of horse teeth are intertwined.
All horses have 12 premolars, 12 molars, and 12 incisors.
Generally, all male equines also have four canine teeth (called tushes) between the molars and incisors, but, few female horses (less than 28%) have canines, and those that do usually have only one or two, which many times are only partially erupted.
A few horses have one to four wolf teeth, which are vestigial premolars, with most of those having only one or two, equally common in male and female horses and much more likely to be on the upper jaw; if present these can cause problems as they can interfere with the horse's bit contact; therefore, wolf teeth are commonly removed.
# Baboons
"Grossly, human speech concatenates syllables, each with a vowel at its core and each vowel flanked by consonants. Each language has its own particular phonology (i.e. its own inventory of vowel and consonant phonemes and patterns of their use), but the phonemes are drawn systematically from a universal superset structured by the anatomy and physiology of the vocal tract and vocal folds. In particular, all the vowels are differently situated within a roughly triangular vocalic space ."
The procedure for acoustic analysis and VLS labeling is shown in the second image down on the right: "(A) Vocalizations in both human and nonhuman primates use the acoustic signal from the vocal folds vibrating at their fundamental frequency (F0). The formant frequencies depend on the configuration of the vocal tract and the lip opening. (B) LPC analysis was used to reveal the formants of each VLS (supplemental information S2 Fig) . (C) A Monte Carlo procedure using an n-tube model normalized for the anatomical measures of the baboons’ vocal tracts then served to generate the MAS (shown by the red line). With this normalized MAS reference, any VLSs could be precisely labeled with the IPA vowel symbols . (D) The VLSs thus labeled correspond to well-documented articulatory configurations with characteristic tongue positions and lip openings. (A-D) Red-&-black dots indicate the corresponding values for this illustrative grunt vocalization, which is classified as ."
"aboons’ wahoos, yaks, barks and other vocalizations evidence of five vowel-like sounds — a sign that the physical capacity for speech may have evolved over much longer timescales than previously thought."
"By comparing the vocal tract of humans and their close primate relatives, researchers can get a sense of which particular traits were necessary for the emergence of speech."
The third image down on the right shows the anatomical "structure of the baboon tongue and muscle recruitment during VLS production: (A) The baboon’s muscle fiber orientation allows tongue motion along two main axes (see also supplemental information S3 Fig). The first axis produces the front/back contrast ⇔ , including the VLS, which requires a constriction in the back of the vocal tract. Movement along this axis uses antagonistic activation of GGam and SG tongue muscles. The second axis produces the ⇔ VLS contrasts by controlling vertical tongue displacement using the GGp and HG tongue muscles. (B) The baboons’ different VLSs can each be explained by recruitment of a unique configuration of tongue muscles. GGa, GGm, GGp: anterior, medium, posterior part of the genioglossus; HG: hyoglossus; SG: styloglossus."
Speech “engages anatomical traits that might leave fossil clues, as well as overt anatomical, physiological, and behavioral aspects for which parallels can be sought in living primates.”
The fourth image down on the right shows an anatomic sagittal view of the head of a female baboon with vocalization organs labeled: "(1) hyoid bone, (2) air sac, (3) thyroid cartilage, (4) epiglottis, (5) arytenoid cartilage, (6) vocal folds and glottis, (7) cricoid cartilage, (8) trachea, (9) lips, (10) incisors, (11) mandible, (12) hard palate, (13) velum, (14) pharyngeal wall, (15-16-17) anterior GGa, medial GGm, and posterior genioglossus GGp,(18) superior longitudinalis, (19) geniohyoid GH, (20) digastric anterior, (21) C1, (22) C2,(23) C3, (24) mid sagittal line of the vocal tract used to infer the tract length and the computation of the MAS. Note the orientation of the fibers of the GGa, GGm and GGp muscles, which approach vertical on the anterior part of the tongue but are effectively horizontal in the posterior part. The fibers of the styloglossus (SG) muscle on the lateral sides of the tongue have approximately the same inclination as those of a human baby . As in humans, the hyoglossus (HG) muscle has two components which are inserted into the body of the hyoid bone and over the entire extent of the great horn. Its fibers are oriented vertically as found in human children. (N.B.: SG and HG are both lateral to the midline, and do not appear on this view.) This anatomical study shows that a baboon’s tongue has the same musculature as a human’s. Regarding shape and proportions, the baboon’s tongue is more similar to that of a child than that of a human adult."
"In large part, human speech uses vowels as the kernel of a sound and places consonants around those vowels. So the number of different vowels you can make is important, because it means you can make a greater variety of potentially meaningful chunks of sound."
"Think about “cat,” “kit,” “cut,” “coat,” “coot,” “keet,” and “caught” — seven words with distinct meanings. Each has a “k” sound at the beginning and a “t” at the end; what separates them is their vowels. Without each of those subtly distinguishable vowels, English speakers wouldn’t be able to tell those words apart."
"Languages have different inventories and patterns of vowel and consonant usage, but they all rely on roughly the same vocal tract shape. And for a long time, many researchers assumed that nonhuman primates couldn’t make vowel-like sounds because their larynxes (or voice boxes) sat much higher in the neck than human larynxes do. That assumption had major implications for theories on the emergence of language, which remains a uniquely human ability."
“This theory has often been used to buttress the theoretical claim of a recent date for language origin, e.g. 70,000-100,000 years ago. It also diverted scientists' interests away from articulated sound in nonhuman primates as a potential homolog of human speech, and thus lent support to less direct explanations of language evolution, involving communicative gestures, complex cognitive or neural functions, or genetics.”
"Lowered larynxes have been found in other animals that have no ability to make vowel sounds. And human babies, who have very high larynxes, can still generate the same vowel range as adults. Scientists have begun to realize, thanks to computer modeling work, that the movement and control of the tongue’s position is actually much more important in making vowel sounds than the height of the larynx."
Formants "are concentrations of acoustic energy around key frequencies in human speech, and their distribution is defined in part by the shape of our vocal tract."
"The individual formants found in a vowel can tell you the configuration of the mouth that made it — for example, whether the lips are rounded, how high the tongue is, and whether the tongue is pushed forward toward the teeth or back in the mouth."
"In human speech, each vowel has a particular blend of formants that make it a unique, easily identifiable sound."
"15 Guinea baboons (12 females and three males) in an outdoor enclosure at the National Center for Scientific Research’s primate center in Rousset-sur-Arc, France."
Five "types of baboon vocalizations to feature formants — grunts, wahoos, barks, yaks and mating calls."
"After analyzing the 1,335 spontaneous vocalizations (and after splitting the wahoos into their wa- and -hoo subunits), the researchers concluded that the recordings held 1,404 “vowel-like segments.”"
"For the ability to make specific vowel-like sounds, it seemed that tongue position really was more important than the larynx’s height."
"The ability to articulate vowel-like sounds, necessary for the development of human speech, was probably shared by the last common ancestor of both humans and baboons some 25 million years ago."
“Whatever the course of the emergence of language and speech, the evidence developed in this study does not support the hypothesis of the recent, sudden, and simultaneous appearance of language and speech in modern Homo sapiens.”
# Dogs
In dogs, the teeth are less likely than humans to form dental caries (cavities) because of the very high pH of dog saliva, which prevents enamel from demineralizing.
Sometimes called cuspids, these teeth are shaped like points (cusps) and are used for tearing and grasping food.
# Rodents
Many rodents such as voles and guinea pigs, but not mice, as well as leporidae like rabbits, have continuously growing molars in addition to incisors.
# Sharks
In cartilaginous fish, such as sharks, the teeth are attached by tough ligaments to the hoops of cartilage] that form the jaw.
# Sea urchins
# Evolution
Teeth appear to have first evolved in sharks, and are not found in the more primitive jawless fish – while lampreys do have tooth-like structures on the tongue, these are in fact, composed of keratin, not of dentine or enamel, and bear no relationship to true teeth. Though "modern" teeth-like structures with dentine and enamel have been found in late conodonts, they are now supposed to have evolved independently of later vertebrates' teeth.
# Genes
The genes governing tooth development in mammals are homologous to those involved in the development of fish scales. Study of a tooth plate of a fossil of the extinct fish Romundina stellina showed that the teeth and scales were made of the same tissues, also found in mammal teeth, lending support to the theory that teeth evolved as a modification of scales.
# Human genes
GeneID: 765 carbonic anhydrase 6 .
"We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) of the carbonic anhydrase VI was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918)."
"The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility."
GeneID: 3479 IGF1 insulin like growth factor 1 .
"The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein."
GeneID: 3480 IGF1R insulin like growth factor 1 receptor .
"IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1."
"The teeth showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation."
GeneID: 7124 TNF tumor necrosis factor .
"Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown."
"TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis."
"Various signaling pathways , such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways."
The "differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway."
# Prehistory
Teeth are a common fossil that occurs in many strata in the history of Draft:rocks on Draft:Earth.
The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k.
# Hypotheses
- The teeth of Tyrannosaurus rex come from the same gene as those of the sea perch, Tautogolabrus adspersus. | Teeth
Editor-In-Chief: Henry A. Hoff
Teeth are found in the mouths of humans and many other animals. The word teeth is the plural of the word tooth. Teeth are of various shapes, sizes and lengths.
Normally adult humans have 32 teeth in their mouth which help chew food.
Teeth have a natural coating which is called enamel.
Necessary care needs be excercised while cleaning or brushing them. Teeth in good condition have aesthetic appeal that attracts and pleases viewers.
# Theoretical teeth
Def. a "hard, calcareous structure present in the mouth of many vertebrate animals, generally used for eating"[1] is called a tooth.
The pattern of incisors, canines, premolars and molars is found only in mammals, and to varying extents, in their evolutionary ancestors, but the numbers of these types of teeth vary greatly between species; zoologists use a standardised dental formula to describe the precise pattern in any given group.[2]
The image on the right is a model of a human molar-like tooth. Its components are labeled:
- Tooth:
- Enamel
- Dentin
- Dental pulp:
- cameral pulp
- root pulp
- Cementum
- Crown
- Cusp
- Sulcus
- Cementoenamel junction or Neck
- Root
- Furcation
- Root apex
- Apical foramen
- Gingival sulcus
- Periodontium:
- Gingiva:
- free or interdental
- marginal
- alveolar
- Periodontal ligament
- Alveolar bone
- Vessels and nerves:
- dental
- periodontal
- alveolar through alveolar canals.
# Visuals
Teeth of humans are small, calcified, hard, whitish structures found in the mouth. They function in [mastication] mechanically breaking down items of food by cutting and crushing them in preparation for swallowing and digestion. The roots of teeth are embedded in the maxilla (upper jaw) or the mandible (lower jaw) and are covered by gingiva or gums. Teeth are made of multiple tissues of varying density and hardness.
# Cetaceans
Like human teeth, whale teeth have polyp-like protrusions located on the root surface of the tooth are made of cementum in both animals, but in human teeth, the protrusions are located on the outside of the root, while in whales the nodule is located on the inside of the pulp chamber, with the roots of human teeth made of cementum on the outer surface, whales have cementum on the entire surface of the tooth with a very small layer of enamel at the tip only seen in older whales where the cementum has been worn away to show the underlying enamel.[3]
# Mammuthus primigenius
On the right is an image of a molar tooth from a specimen (No. 201669, ELM G319:2) of the woolly mammoth Mammuthus primigenius. The tooth was collected about January 17, 2006, near Puurmani, Estonia, from a Quaternary deposit and the record for the tooth inserted into the collection on October 18, 2008.
The image on the right is of a lophodont cheek molar.
# Sahelanthropus tchadensis
"Sahelanthropus tchadensis is one of the oldest known species in the human family tree. This species lived sometime between 7 and 6 million years ago in West-Central Africa (Chad). Walking upright may have helped this species survive in diverse habitats, including forests and grasslands. Although we have only cranial material from Sahelanthropus, studies so far show this species had a combination of ape-like and human-like features. Ape-like features included a small brain (even slightly smaller than a chimpanzee’s), sloping face, very prominent browridges, and elongated skull. Human-like features included small canine teeth, a short middle part of the face, and a spinal cord opening underneath the skull instead of towards the back as seen in non-bipedal apes."[4]
"Some of the oldest evidence of a humanlike species moving about in an upright position comes from Sahelanthropus. The foramen magnum (the large opening where the spinal cord exits out of the cranium from the brain) is located further forward (on the underside of the cranium) than in apes or any other primate except humans. This feature indicates that the head of Sahelanthropus was held on an upright body, probably associated with walking on two legs."[4]
"The first (and, so far, only) fossils of Sahelanthropus are nine cranial specimens from northern Chad. A research team of scientists led by French paleontologist Michael Brunet uncovered the fossils in 2001, including the type specimen TM 266-1-606-1. Before 2001, early humans in Africa had only been found in the Great Rift Valley in East Africa and sites in South Africa, so the discovery of Sahelanthropus fossils in West-Central Africa shows that the earliest humans were more widely distributed than previously thought."[4]
# Orrorin tugenensis
"Living around 6 million years ago, Orrorin tugenensis is the one of the oldest early humans on our family tree. Individuals of this species were approximately the size of a chimpanzee and had small teeth with thick enamel, similar to modern humans. The most important fossil of this species is an upper femur, showing evidence of bone buildup typical of a biped - so Orrorin tugenensis individuals climbed trees but also probably walked upright with two legs on the ground."[5]
"A research team led by French paleontologist Brigitte Senut and French geologist Martin Pickford discovered this species in the Tugen Hills region of central Kenya. They found more than a dozen early human fossils dating between about 6.2 million and 6.0 million years old. Because of its novel combination of ape and human traits, the researchers gave a new genus and species name to these fossils, Orrorin tugenensis, which in the local language means “original man in the Tugen region.” So far, Orrorin tugenensis is the only species in the genus Orrorin."[5]
"Orrorin’s femur (thigh bone) and humerus (upper arm bone) are about 1.5 times larger than those of Lucy’s (AL 288-1). Therefore, scientists estimate that Orrorin would have been 1.5 times larger than Au. afarensis, suggesting a size similar to a female chimpanzee, between about 30 and 50 kg."[5]
# Horse
An adult horse has between 36 and 44 teeth, where the enamel and dentin layers of horse teeth are intertwined.[6]
All horses have 12 premolars, 12 molars, and 12 incisors.[7]
Generally, all male equines also have four canine teeth (called tushes) between the molars and incisors, but, few female horses (less than 28%) have canines, and those that do usually have only one or two, which many times are only partially erupted.[8]
A few horses have one to four wolf teeth, which are vestigial premolars, with most of those having only one or two, equally common in male and female horses and much more likely to be on the upper jaw; if present these can cause problems as they can interfere with the horse's bit contact; therefore, wolf teeth are commonly removed.[7]
# Baboons
"Grossly, human speech concatenates syllables, each with a vowel at its core and each vowel flanked by consonants. Each language has its own particular phonology (i.e. its own inventory of vowel and consonant phonemes and patterns of their use), but the phonemes are drawn systematically from a universal superset structured by the anatomy and physiology of the vocal tract and vocal folds. In particular, all the vowels are differently situated within a roughly triangular [i a u] vocalic space [1,2]."[9]
The procedure for acoustic analysis and VLS labeling is shown in the second image down on the right: "(A) Vocalizations in both human and nonhuman primates use the acoustic signal from the vocal folds vibrating at their fundamental frequency (F0). The formant frequencies depend on the configuration of the vocal tract and the lip opening. (B) [Linear Predictive Coding] LPC analysis was used to reveal the formants of each [vowel like segments] VLS (supplemental information S2 Fig) [28,29]. (C) A Monte Carlo procedure using an n-tube model normalized for the anatomical measures of the baboons’ vocal tracts then served to generate the [Maximal Acoustic Space] MAS (shown by the red line). With this normalized MAS reference, any VLSs could be precisely labeled with the [International Phonetic Alphabet] IPA vowel symbols [30,31]. (D) The VLSs thus labeled correspond to well-documented articulatory configurations with characteristic tongue positions and lip openings. (A-D) Red-&-black dots indicate the corresponding values for this illustrative grunt vocalization, which is classified as [u]."[9]
"[B]aboons’ wahoos, yaks, barks and other vocalizations [contain] evidence of five vowel-like sounds — a sign that the physical capacity for speech may have evolved over much longer timescales than previously thought."[10]
"By comparing the vocal tract of humans and their close primate relatives, researchers can get a sense of which particular traits were necessary for the emergence of speech."[10]
The third image down on the right shows the anatomical "structure of the baboon tongue and muscle recruitment during VLS production: (A) The baboon’s muscle fiber orientation allows tongue motion along two main axes (see also supplemental information S3 Fig). The first axis produces the front/back contrast [æ] ⇔ [u ɔ], including the [u] VLS, which requires a constriction in the back of the vocal tract. Movement along this axis uses antagonistic activation of GGam and SG tongue muscles. The second axis produces the [ɑ] ⇔ [ɨ] VLS contrasts by controlling vertical tongue displacement using the GGp and HG tongue muscles. (B) The baboons’ different VLSs can each be explained by recruitment of a unique configuration of tongue muscles. GGa, GGm, GGp: anterior, medium, posterior part of the genioglossus; HG: hyoglossus; SG: styloglossus."[9]
Speech “engages anatomical traits that might leave fossil clues, as well as overt anatomical, physiological, and behavioral aspects for which parallels can be sought in living primates.” [9]
The fourth image down on the right shows an anatomic sagittal view of the head of a female baboon with vocalization organs labeled: "(1) hyoid bone, (2) air sac, (3) thyroid cartilage, (4) epiglottis, (5) arytenoid cartilage, (6) vocal folds and glottis, (7) cricoid cartilage, (8) trachea, (9) lips, (10) incisors, (11) mandible, (12) hard palate, (13) velum, (14) pharyngeal wall, (15-16-17) anterior GGa, medial GGm, and posterior genioglossus GGp,(18) superior longitudinalis, (19) geniohyoid GH, (20) digastric anterior, (21) C1, (22) C2,(23) C3, (24) mid sagittal line of the vocal tract used to infer the tract length and the computation of the MAS. Note the orientation of the fibers of the GGa, GGm and GGp muscles, which approach vertical on the anterior part of the tongue but are effectively horizontal in the posterior part. The fibers of the styloglossus (SG) muscle on the lateral sides of the tongue have approximately the same inclination as those of a human baby [10]. As in humans, the hyoglossus (HG) muscle has two components which are inserted into the body of the hyoid bone and over the entire extent of the great horn. Its fibers are oriented vertically as found in human children. (N.B.: SG and HG are both lateral to the midline, and do not appear on this view.) This anatomical study shows that a baboon’s tongue has the same musculature as a human’s. Regarding shape and proportions, the baboon’s tongue is more similar to that of a child than that of a human adult."[9]
"In large part, human speech uses vowels as the kernel of a sound and places consonants around those vowels. So the number of different vowels you can make is important, because it means you can make a greater variety of potentially meaningful chunks of sound."[10]
"Think about “cat,” “kit,” “cut,” “coat,” “coot,” “keet,” and “caught” — seven words with distinct meanings. Each has a “k” sound at the beginning and a “t” at the end; what separates them is their vowels. Without each of those subtly distinguishable vowels, English speakers wouldn’t be able to tell those words apart."[10]
"Languages have different inventories and patterns of vowel and consonant usage, but they all rely on roughly the same vocal tract shape. And for a long time, many researchers assumed that nonhuman primates couldn’t make vowel-like sounds because their larynxes (or voice boxes) sat much higher in the neck than human larynxes do. That assumption had major implications for theories on the emergence of language, which remains a uniquely human ability."[10]
“This theory has often been used to buttress the theoretical claim of a recent date for language origin, e.g. 70,000-100,000 years ago. It also diverted scientists' interests away from articulated sound in nonhuman primates as a potential homolog of human speech, and thus lent support to less direct explanations of language evolution, involving communicative gestures, complex cognitive or neural functions, or genetics.”[9]
"Lowered larynxes have been found in other animals that have no ability to make vowel sounds. And human babies, who have very high larynxes, can still generate the same vowel range as adults. Scientists have begun to realize, thanks to computer modeling work, that the movement and control of the tongue’s position is actually much more important in making vowel sounds than the height of the larynx."[10]
Formants "are concentrations of acoustic energy around key frequencies in human speech, and their distribution is defined in part by the shape of our vocal tract."[10]
"The individual formants found in a vowel can tell you the configuration of the mouth that made it — for example, whether the lips are rounded, how high the tongue is, and whether the tongue is pushed forward toward the teeth or back in the mouth."[10]
"In human speech, each vowel has a particular blend of formants that make it a unique, easily identifiable sound."[10]
"15 Guinea baboons (12 females and three males) [such as those in the image on the right, live] in an outdoor enclosure at the National Center for Scientific Research’s primate center in Rousset-sur-Arc, France."[10]
Five "types of baboon vocalizations [appear] to feature formants — grunts, wahoos, barks, yaks and mating calls."[10]
"After analyzing the 1,335 spontaneous vocalizations (and after splitting the wahoos into their wa- and -hoo subunits), the researchers concluded that the recordings held 1,404 “vowel-like segments.”"[10]
"For the ability to make specific vowel-like sounds, it seemed that tongue position really was more important than the larynx’s height."[10]
"The ability to articulate vowel-like sounds, necessary for the development of human speech, was probably shared by the last common ancestor of both humans and baboons [among the Cercopithecoidea] some 25 million years ago."[10]
“Whatever the course of the emergence of language and speech, the evidence developed in this study does not support the hypothesis of the recent, sudden, and simultaneous appearance of language and speech in modern Homo sapiens.”[9]
# Dogs
In dogs, the teeth are less likely than humans to form dental caries (cavities) because of the very high pH of dog saliva, which prevents enamel from demineralizing.[11]
Sometimes called cuspids, these teeth are shaped like points (cusps) and are used for tearing and grasping food.[12]
# Rodents
Many rodents such as voles and guinea pigs, but not mice, as well as leporidae like rabbits, have continuously growing molars in addition to incisors.[13][14]
# Sharks
In cartilaginous fish, such as sharks, the teeth are attached by tough ligaments to the hoops of cartilage] that form the jaw.[2]
# Sea urchins
# Evolution
Teeth appear to have first evolved in sharks, and are not found in the more primitive jawless fish – while lampreys do have tooth-like structures on the tongue, these are in fact, composed of keratin, not of dentine or enamel, and bear no relationship to true teeth.[2] Though "modern" teeth-like structures with dentine and enamel have been found in late conodonts, they are now supposed to have evolved independently of later vertebrates' teeth.[15][16]
# Genes
The genes governing tooth development in mammals are homologous to those involved in the development of fish scales.[17] Study of a tooth plate of a fossil of the extinct fish Romundina stellina showed that the teeth and scales were made of the same tissues, also found in mammal teeth, lending support to the theory that teeth evolved as a modification of scales.[18]
# Human genes
GeneID: 765 carbonic anhydrase 6 [ Homo sapiens (human) ].
"We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) of the carbonic anhydrase VI was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918)."[19]
"The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility."[19]
GeneID: 3479 IGF1 insulin like growth factor 1 [ Homo sapiens (human) ].
"The protein encoded by this gene is similar to insulin in function and structure and is a member of a family of proteins involved in mediating growth and development. The encoded protein is processed from a precursor, bound by a specific receptor, and secreted. Defects in this gene are a cause of insulin-like growth factor I deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar processing to generate mature protein."[20]
GeneID: 3480 IGF1R insulin like growth factor 1 receptor [ Homo sapiens (human) ].
"IGF-1 regulates the metabolism of hard dental tissue through binding to the IGF-1 receptor on target cells. Furthermore, IGF-binding-protein-3 promotes the accessibility of IGF-1."[21]
"The teeth [showing ongoing development] showed significantly stronger expression of IGF-1 and IGF-1R. The major sources of all of the proteins investigated immunohistochemically in sections of wisdom teeth were odontoblasts, cementoblasts and cell colonies in the pulpal mesenchyme. [...] members of the IGF-1 family are involved in the late stage of tooth development and the process of pulpal differentiation."[21]
GeneID: 7124 TNF tumor necrosis factor [ Homo sapiens (human) ].
"Tumor necrosis factor-α (TNF-α) is involved in various inflammatory processes, including periodontitis. Although the influences of TNF-α on periodontal ligament fibroblasts and osteoblasts have been widely documented, its effects on cementoblasts, the cells responsible for cementum production, remain largely unknown."[22]
"TNF-α suppressed the mineralization ability of cementoblasts by inhibiting differentiation and inducing apoptosis."[22]
"Various signaling pathways [image on the right], such as p53, PP2AC, p38, Erk1/2, JNK, PI3K-Akt, and NF-κB, were activated during this process. The use of a specific inhibitor and siRNA transfection confirmed that the effects of TNF-α on differentiation and apoptosis in cementoblasts were partially abrogated by inhibiting p53 activity. By contrast, the effects of TNF-α were even exacerbated by the inhibition of the p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways. Moreover, p53 activity was further enhanced by blocking the p38, Erk1/2, JNK, and PI3K-Akt signaling pathways."[22]
The "differentiation inhibition and apoptosis in cementoblasts induced by TNF-α were partially dependent on p53 activity. The p38, Erk1/2, JNK, PI3K-Akt, and NF-κB pathways were also activated but acted as balancing players to limit rather than conduct the negative effects of TNF-α. These balancing effects were dependent, or at least partially dependent, on p53, except for the NF-κB pathway."[22]
# Prehistory
Teeth are a common fossil that occurs in many strata in the history of Draft:rocks on Draft:Earth.
The prehistory period dates from around 7 x 106 b2k to about 7,000 b2k.
# Hypotheses
- The teeth of Tyrannosaurus rex come from the same gene as those of the sea perch, Tautogolabrus adspersus. | https://www.wikidoc.org/index.php/Teeth | |
2a78573c97298ff3275826a578c75162de5c4558 | wikidoc | tera- | tera-
tera- (symbol: T) is a prefix in the SI system of units denoting 1012, or 1,000,000,000,000 (1 million million).
Confirmed in 1960, it comes from the Greek τέρας, meaning monster. It also bears a resemblance to the Greek prefix τετρα- meaning four; the coincidence of it signifying the fourth power of 1000 served as a model for the higher-order prefixes peta-, exa-, zetta- and yotta-, all of which are deliberately distorted forms of the Latin or Greek roots for the corresponding powers (fifth to eighth respectively) of 1000.
In computer science tera- can sometimes mean 1,099,511,627,776 (240) instead of 1,000,000,000,000, especially in the term terabyte. To avoid this ambiguity, the binary prefix tebi- has been introduced to signify 240, but this, in common with the other binary prefixes, is not currently in general use. | tera-
tera- (symbol: T) is a prefix in the SI system of units denoting 1012, or 1,000,000,000,000 (1 million million).
Confirmed in 1960, it comes from the Greek τέρας, meaning monster.[1] It also bears a resemblance to the Greek prefix τετρα- meaning four; the coincidence of it signifying the fourth power of 1000 served as a model for the higher-order prefixes peta-, exa-, zetta- and yotta-, all of which are deliberately distorted forms of the Latin or Greek roots for the corresponding powers (fifth to eighth respectively) of 1000.
In computer science tera- can sometimes mean 1,099,511,627,776 (240) instead of 1,000,000,000,000, especially in the term terabyte. To avoid this ambiguity, the binary prefix tebi- has been introduced to signify 240, but this, in common with the other binary prefixes, is not currently in general use.
Template:SI prefixes | https://www.wikidoc.org/index.php/Tera |
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