5tx4
From Proteopedia
Derivative of mouse TGF-beta2, with a deletion of residues 52-71 and K25R, R26K, L51R, A74K, C77S, L89V, I92V, K94R T95K, I98V single amino acid substitutions, bound to human TGF-beta type II receptor ectodomain residues 15-130
Structural highlights
DiseaseTGFR2_HUMAN Defects in TGFBR2 are the cause of hereditary non-polyposis colorectal cancer type 6 (HNPCC6) [MIM:614331. Mutations in more than one gene locus can be involved alone or in combination in the production of the HNPCC phenotype (also called Lynch syndrome). Most families with clinically recognized HNPCC have mutations in either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly inherited disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early onset colorectal carcinoma (CRC) and extra-colonic cancers of the gastrointestinal, urological and female reproductive tracts. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world, and accounts for 15% of all colon cancers. Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Clinically, HNPCC is often divided into two subgroups. Type I: hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II: patients have an increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical HNPCC is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term "suspected HNPCC" or "incomplete HNPCC" can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. HNPCC6 is a type of colorectal cancer complying with the clinical criteria of HNPCC, except that the onset of cancer was beyond 50 years of age in all cases.[1] Defects in TGFBR2 are a cause of esophageal cancer (ESCR) [MIM:133239. Defects in TGFBR2 are the cause of Loeys-Dietz syndrome type 1B (LDS1B) [MIM:610168. LDS1 is an aortic aneurysm syndrome with widespread systemic involvement. The disorder is characterized by arterial tortuosity and aneurysms, craniosynostosis, hypertelorism, and bifid uvula or cleft palate. Other findings include exotropy, micrognathia and retrognathia, structural brain abnormalities, intellectual deficit, congenital heart disease, translucent skin, joint hyperlaxity and aneurysm with dissection throughout the arterial tree.[2] [3] [4] [5] [6] [7] Defects in TGFBR2 are the cause of Loeys-Dietz syndrome type 2B (LDS2B) [MIM:610380. An aortic aneurysm syndrome with widespread systemic involvement. Physical findings include prominent joint laxity, easy bruising, wide and atrophic scars, velvety and translucent skin with easily visible veins, spontaneous rupture of the spleen or bowel, diffuse arterial aneurysms and dissections, and catastrophic complications of pregnancy, including rupture of the gravid uterus and the arteries, either during pregnancy or in the immediate postpartum period. LDS2 is characterized by the absence of craniofacial abnormalities with the exception of bifid uvula that can be present in some patients. Note=TGFBR2 mutations Cys-460 and His-460 have been reported to be associated with thoracic aortic aneurysms and dissection (TAAD). This phenotype, also known as thoracic aortic aneurysms type 3 (AAT3), is distinguised from LDS2B by having aneurysms restricted to thoracic aorta. As individuals carrying these mutations also exhibit descending aortic disease and aneurysms of other arteries (PubMed:16027248), they have been considered as LDS2B by the OMIM resource. FunctionTGFR2_HUMAN Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3. Transduces the TGFB1, TGFB2 and TGFB3 signal from the cell surface to the cytoplasm and is thus regulating a plethora of physiological and pathological processes including cell cycle arrest in epithelial and hematopoietic cells, control of mesenchymal cell proliferation and differentiation, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. The formation of the receptor complex composed of 2 TGFBR1 and 2 TGFBR2 molecules symmetrically bound to the cytokine dimer results in the phosphorylation and the activation of TGFRB1 by the constitutively active TGFBR2. Activated TGFBR1 phosphorylates SMAD2 which dissociates from the receptor and interacts with SMAD4. The SMAD2-SMAD4 complex is subsequently translocated to the nucleus where it modulates the transcription of the TGF-beta-regulated genes. This constitutes the canonical SMAD-dependent TGF-beta signaling cascade. Also involved in non-canonical, SMAD-independent TGF-beta signaling pathways.[8] Publication Abstract from PubMedThe transforming growth factor beta isoforms, TGF-beta1, -beta2, and -beta3 are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-beta pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. In spite of the known importance of TGF-betas in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-beta monomer, lacking the heel helix, a structural motif essential for binding the TGF-beta type I receptor, TbetaRI, but dispensible for binding the other receptor required for TGF-beta signaling, the TGF-beta type II receptor, TbetaRII, as an alternative therapeutic modality for blocking TGF-beta signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-beta monomers and bound TbetaRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-beta signaling with a Ki of 20 - 70 nM. Investigation of the mechanism showed that the high affinity of the engineered monomer for TbetaRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TbetaRI, enabled it to bind endogenous TbetaRII, but prevented it from binding and recruiting TbetaRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-beta signaling, and may inform similar modifications of other TGF-beta family members. An Engineered TGF-beta Monomer that Functions as a Dominant Negative to Block TGF-beta Signaling.,Kim SK, Barron L, Hinck CS, Petrunak EM, Cano KE, Thangirala A, Iskra B, Brothers M, Vonberg M, Leal B, Richter B, Kodali R, Taylor AB, Du S, Barnes CO, Sulea T, Calero G, Hart PJ, Hart MJ, Demeler B, Hinck AP J Biol Chem. 2017 Feb 22. pii: jbc.M116.768754. doi: 10.1074/jbc.M116.768754. PMID:28228478[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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