5ffo
From Proteopedia
Integrin alpha V beta 6 in complex with pro-TGF-beta
Structural highlights
Disease[TGFB1_HUMAN] Defects in TGFB1 are the cause of Camurati-Engelmann disease (CE) [MIM:131300]; also known as progressive diaphyseal dysplasia 1 (DPD1). CE is an autosomal dominant disorder characterized by hyperostosis and sclerosis of the diaphyses of long bones. The disease typically presents in early childhood with pain, muscular weakness and waddling gait, and in some cases other features such as exophthalmos, facial paralysis, hearing difficulties and loss of vision.[1] [2] [3] [4] [5] [ITB6_HUMAN] Hypocalcified amelogenesis imperfecta;Hypoplastic amelogenesis imperfecta. Function[ITAV_HUMAN] The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. [TGFB1_HUMAN] Multifunctional protein that controls proliferation, differentiation and other functions in many cell types. Many cells synthesize TGFB1 and have specific receptors for it. It positively and negatively regulates many other growth factors. It plays an important role in bone remodeling as it is a potent stimulator of osteoblastic bone formation, causing chemotaxis, proliferation and differentiation in committed osteoblasts. [ITB6_HUMAN] Integrin alpha-V/beta-6 is a receptor for fibronectin and cytotactin. It recognizes the sequence R-G-D in its ligands. Internalisation of integrin alpha-V/beta-6 via clathrin-mediated endocytosis promotes carcinoma cell invasion.[6] Publication Abstract from PubMedIntegrins are adhesion receptors that transmit force across the plasma membrane between extracellular ligands and the actin cytoskeleton. In activation of the transforming growth factor-beta1 precursor (pro-TGF-beta1), integrins bind to the prodomain, apply force, and release the TGF-beta growth factor. However, we know little about how integrins bind macromolecular ligands in the extracellular matrix or transmit force to them. Here we show how integrin alphaVbeta6 binds pro-TGF-beta1 in an orientation biologically relevant for force-dependent release of TGF-beta from latency. The conformation of the prodomain integrin-binding motif differs in the presence and absence of integrin binding; differences extend well outside the interface and illustrate how integrins can remodel extracellular matrix. Remodelled residues outside the interface stabilize the integrin-bound conformation, adopt a conformation similar to earlier-evolving family members, and show how macromolecular components outside the binding motif contribute to integrin recognition. Regions in and outside the highly interdigitated interface stabilize a specific integrin/pro-TGF-beta orientation that defines the pathway through these macromolecules which actin-cytoskeleton-generated tensile force takes when applied through the integrin beta-subunit. Simulations of force-dependent activation of TGF-beta demonstrate evolutionary specializations for force application through the TGF-beta prodomain and through the beta- and not alpha-subunit of the integrin. Force interacts with macromolecular structure in activation of TGF-beta.,Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C, Engen JR, Springer TA Nature. 2017 Feb 2;542(7639):55-59. doi: 10.1038/nature21035. Epub 2017 Jan 25. PMID:28117447[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Dong, X | Springer, T A | Zhao, B | Cell adhesion | Integrin | Tgf-beta
