User:Gabriel Zarzana Espinoza/Sandbox 1
From Proteopedia
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== Function == | == Function == | ||
| - | The transforming growth factor beta 1 receptor is a protein responsible for the action signal initiation of the transforming growth factor beta by phosphorylating cytoplasmic proteins Smads at the C-terminus, causing these proteins to form a heteromeric complex. This complex will move to the nucleus to regulate the transcription of genes related to this factor, such as genes that promote proliferation, differentiation, apoptosis or cell migration, and the development of fibrosis in several organs, among others. | + | The transforming growth factor beta 1 (TGFBR1) receptor is a protein responsible for the action signal initiation of the transforming growth factor beta by phosphorylating cytoplasmic proteins Smads at the C-terminus, causing these proteins to form a heteromeric complex. This complex will move to the nucleus to regulate the transcription of genes related to this factor, such as genes that promote proliferation, differentiation, apoptosis or cell migration, and the development of fibrosis in several organs, among others. |
This receptor is the product of the translation and transcription of the TGFBR1 gene, also known as ALK5, which is located at the position 22.33 on the long arm (q) of chromosome 9 of organisms belonging to the ''Homo sapiens'' species (Human). This gene is expressed through all the body, although it is found more abundantly in the placenta and just barely in the brain and the heart. | This receptor is the product of the translation and transcription of the TGFBR1 gene, also known as ALK5, which is located at the position 22.33 on the long arm (q) of chromosome 9 of organisms belonging to the ''Homo sapiens'' species (Human). This gene is expressed through all the body, although it is found more abundantly in the placenta and just barely in the brain and the heart. | ||
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== Diseases == | == Diseases == | ||
| - | Mutations in the gene | + | Mutations in the TGFBR1 gene can result in the development of Loeys-Dietz syndrome 1 (LDS1). This type of aortic aneurysm syndrome, which is systemically widespread, is one of the most common Loeys-Dietz syndromes, along with type 2. It is internally characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate; and externally by prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel. Some patients may also have craniosynostosis, exotropia, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, and even problems in the immune system, including food allergies, asthma, and inflammatory disorders, such as eczema or inflammatory bowel disease <ref>Loeys-Dietz syndrome. Genetics Home Reference, U.S National Library of Medicine (2020). https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome</ref>. |
| - | This disease | + | This disease presents an autosomal dominant pattern of inheritance. However, about 75% of the cases happen because of new mutations and therefore manifest on individuals in families without the disease. This proportion may be explained by the fact that women with this disease are likely to have severe pregnancy complications, such as rupture of the gravid uterus and the arteries, either during pregnancy or just after childbirth. These complications reduce the survival rate of both mother and infant, which may be one of the reasons as to why this disease is rarely inherited despite its dominant behavior. |
| - | Diverse mutations in ALK-5 can lead to multiple cancers. One of these | + | Diverse mutations in ALK-5 can lead to multiple cancers. One of these is the multiple self-healing squamous epithelioma (MSSE). This is a form of skin cancer, also known as the Ferguson-Smith disease, characterized by the formation of multiple invasive and painless skin tumors that grow uncontrollably mostly in sun-exposed tissues for a few months, before shrinking and dying off for unkown reasons, leaving a deep and pitted scar <ref>D'Alessandro, M., et al. Multiple Self-Healing Squamous Epithelioma in Different Ethnic Groups: More than a Founder Mutation Disorder?, Journal of Investigative Dermatology, Volume 127, Issue 10, 2007, Pages 2336-2344, ISSN 0022-202X. https://doi.org/10.1038/sj.jid.5700914 DOI: 10.1038/sj.jid.5700914 </ref>. This disease presents an autosomal dominant inheritance and is common in Scottish families. The symptoms extend through all one's life, though the age in which the first tumor appears is variable, happening between 8 and 62 years-old. |
| + | |||
| + | There is also evidence that points to the development of breast cancer due to mutation in the gene that encodes for this protein. TGFBR1*6A is a common hypomorphic variant of TGFBR1 and it has been particularly associated with increased risk for breast cancer <ref>PMID: 21461994</ref>. | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 06:34, 21 June 2020
Contents |
Transforming Growth Factor Beta 1 Receptor
This page is about the transforming growth factor beta 1 receptor, a protein important to signal the actions of the transforming growth factor 1.
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Function
The transforming growth factor beta 1 (TGFBR1) receptor is a protein responsible for the action signal initiation of the transforming growth factor beta by phosphorylating cytoplasmic proteins Smads at the C-terminus, causing these proteins to form a heteromeric complex. This complex will move to the nucleus to regulate the transcription of genes related to this factor, such as genes that promote proliferation, differentiation, apoptosis or cell migration, and the development of fibrosis in several organs, among others. This receptor is the product of the translation and transcription of the TGFBR1 gene, also known as ALK5, which is located at the position 22.33 on the long arm (q) of chromosome 9 of organisms belonging to the Homo sapiens species (Human). This gene is expressed through all the body, although it is found more abundantly in the placenta and just barely in the brain and the heart.
Structural Highlights
This protein is an activin-type kinase receptor belonging to the heterotetrameric receptor complex, constituted by two of these and two beta 2 receptors, to which the transforming growth factor binds. This beta 1 receptor has a similar structure to that of the beta 2 receptor, with both being transmembrane serine/threonine kinase receptors and having: an extracellular cysteine-rich involved in ligand binding; a transmembrane helix; and an intracellular C-terminal cytoplasmic kinase domain [1]. In beta 1 receptors, the kinase domain, mostly a helix, adapts an inactive conformation, distorting and, thus, damaging the integrity of the ATP-binding site by constricting the phosphate and magnesium recognition pocket.
In its N-terminal, the beta 1 receptors possess a smaller N lobe, a larger C lobe and a GS region/domain. The N lobe, dominated by a twisted, five-stranded β sheet, is involved in ATP binding, but it also contains an insertion between strands β4 and β5 (the L45 loop, that extends out into solution to interact with other protein) that determines Smad substrate specificity. At the same time, the C lobe, largely helical (and, thus, why also called alfa C helix), is required for substrate recognition, while the GS region is a regulatory segment.
This segment is formed by the alfa GS1 helix, which is amphiphilic, and the alfa GS2 helix, that is the hydrophobic core of the protein. This second helix contacts both the beta sheet of N lobe and the first helix, which connects to the C lobe - thus, making the GS segment a region located between the two lobes of the N-terminal. The connection of the two helices, in its turn, is made by a loop composed by a conserved sequence of 185TTSGSGSGLP194 (COLOCAR OS NÚMEROS PARA CIMA). This loop is the most important region of the beta 1 receptor, because it is this region that is phosphorylated in its serine and threonine residues by the beta 2 receptor of the heterotetrameric complex when these is linked to the growth factor. Like that, the beta 1 receptor is activated and, in turn, transmits the factor signal, thus, phosphorylating, and so activating, Smad transcription factors. Studies claim that the substitution of the Thr residue of this loop with aspartate or glutamate turns the beta 1 receptor constitutively active, meaning it would not depend in phosphorylation by the beta 2 receptor to function.
(DETERMINAR ONDE SE LOCALIZA E O QUE FAZ: ACTIVATION SEGMENT AND CATALYTIC SEGMENT - possivelmente, eles se encontram na porção transmembrana da rpoteína)
The activation segment of this protein is a beta hairpin composed by the strands beta 9 and beta 10, supported by the alfa F helix extension of the C-terminal. Together with beta 6, this activation segment forms a stranded sheet that stabilizes the rotated conformation of the C lobe. This stabilization is done by the van der Walls interactions, between Ile-248 and Val-252 from the C lobe and Ile-329 and Pro-327 from the beta 6, and hydrogen bonds between Arg-357 from C lobe and Thr-251 from beta 9. At the same time, it binds to the N lobe via van der Walls interactions between its aliphatic portion of Arg-372 and the beta sheet's side-chain of Phe-216. This side-chain of Phe-216 is a loop, known as the phosphate binding loop of the protein, that connects beta 1 and beta 2.
Diseases
Mutations in the TGFBR1 gene can result in the development of Loeys-Dietz syndrome 1 (LDS1). This type of aortic aneurysm syndrome, which is systemically widespread, is one of the most common Loeys-Dietz syndromes, along with type 2. It is internally characterized by arterial tortuosity and aneurysms, hypertelorism, and bifid uvula or cleft palate; and externally by prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel. Some patients may also have craniosynostosis, exotropia, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, and even problems in the immune system, including food allergies, asthma, and inflammatory disorders, such as eczema or inflammatory bowel disease [2]. This disease presents an autosomal dominant pattern of inheritance. However, about 75% of the cases happen because of new mutations and therefore manifest on individuals in families without the disease. This proportion may be explained by the fact that women with this disease are likely to have severe pregnancy complications, such as rupture of the gravid uterus and the arteries, either during pregnancy or just after childbirth. These complications reduce the survival rate of both mother and infant, which may be one of the reasons as to why this disease is rarely inherited despite its dominant behavior.
Diverse mutations in ALK-5 can lead to multiple cancers. One of these is the multiple self-healing squamous epithelioma (MSSE). This is a form of skin cancer, also known as the Ferguson-Smith disease, characterized by the formation of multiple invasive and painless skin tumors that grow uncontrollably mostly in sun-exposed tissues for a few months, before shrinking and dying off for unkown reasons, leaving a deep and pitted scar [3]. This disease presents an autosomal dominant inheritance and is common in Scottish families. The symptoms extend through all one's life, though the age in which the first tumor appears is variable, happening between 8 and 62 years-old.
There is also evidence that points to the development of breast cancer due to mutation in the gene that encodes for this protein. TGFBR1*6A is a common hypomorphic variant of TGFBR1 and it has been particularly associated with increased risk for breast cancer [4].
References
- ↑ Huse, M., et al. Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12. Cell, Volume 96, Issue 3, 425 - 436 (1999). https://doi.org/10.1016/S0092-8674(00)80555-3 DOI: 10.1016/S0092-8674(00)80555-3
- ↑ Loeys-Dietz syndrome. Genetics Home Reference, U.S National Library of Medicine (2020). https://ghr.nlm.nih.gov/condition/loeys-dietz-syndrome
- ↑ D'Alessandro, M., et al. Multiple Self-Healing Squamous Epithelioma in Different Ethnic Groups: More than a Founder Mutation Disorder?, Journal of Investigative Dermatology, Volume 127, Issue 10, 2007, Pages 2336-2344, ISSN 0022-202X. https://doi.org/10.1038/sj.jid.5700914 DOI: 10.1038/sj.jid.5700914
- ↑ Moore-Smith L, Pasche B. TGFBR1 signaling and breast cancer. J Mammary Gland Biol Neoplasia. 2011 Jun;16(2):89-95. doi:, 10.1007/s10911-011-9216-2. Epub 2011 Apr 5. PMID:21461994 doi:http://dx.doi.org/10.1007/s10911-011-9216-2
