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Function
The transforming growth factor beta 1 receptor is a protein that initiates the action signal of this factor 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 some specific genes of this factor, such as genes for: 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. This gene is expressed through all the body, abundantly in the placenta but only 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 N-terminal domain involved in ligand binding; a transmembrane helix; and a C-terminal cytoplasmic kinase domain. In beta 1 receptors, the kinase domain, mostly an helix, adapts an anactive 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, that is amphiphatic, 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 conection 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 hidrogen 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.
Disease
Mutations in the gene that codifies this protein, unknown exactly where, can cause the Loeys-Dietz syndrome 1, shortly known as LDS1. This type of aortic aneurysm syndrome, with widespread systemic involvement, is one of the most common, along with the type 2. It is characterized, internally, 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, exotropy, 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.
This disease has an autosomal dominant pattern of inheritance, but about 75% of the cases happen because of new gene mutations, meaning it happens on people of families in witch no one else has the disease. This interesting data may be explained by the fact that women with this disease will present catastrophic complications in pregnancy, such as the rupture of the gravid uterus and the arteries, either during pregnancy or righ after child-birth. These complications surely reduce the survival rate of both mother and baby, which may be one of the reasons why, although an autosomal dominant disease, most people don't inherit it.
Diverse mutations in ALK-5 can lead to cancer. One of these cancers is the multiple self-healing squamous epithelioma (MSSE). This is a skin cancer, as 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 pittied scar. This disease is inherited as an autosomal dominant trait, it is comum in Scottish families and it happens through all one's life, though the age in which the first tumour appear is variable, between 8 and 62 years-old.
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