6gff | pdb_00006gff

Structure of GARP (LRRC32) in complex with latent TGF-beta1 and MHG-8 Fab

spinqualitylabelsall models 6gff, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6gff is a 14 chain structure with sequence from [1] and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: BMA, MAN, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Function [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. [LRC32_HUMAN] Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space (PubMed:19750484, PubMed:19651619, PubMed:22278742). Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta (PubMed:22278742). Able to outcompete LTBP1 for binding to LAP regulatory chain of TGF-beta (PubMed:22278742). Controls activation of TGF-beta-1 (TGFB1) on the surface of activated regulatory T-cells (Tregs) (PubMed:19750484, PubMed:19651619). Required for epithelial fusion during palate development by regulating activation of TGF-beta-3 (TGFB3) (By similarity).[UniProtKB:G3XA59] Publication Abstract from PubMed Transforming growth factor-beta1 (TGF-beta1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-beta1 presented by GARP to integrin alphaVbeta8 on their surface. We solved the crystal structure of GARP:latent TGF-beta1 bound to an antibody that stabilizes the complex and blocks release of active TGF-beta1. This reveals how GARP exploits an unusual medley of interactions, including fold complementation by the N terminus of TGF-beta1, to chaperone and orient the cytokine for binding and activation by alphaVbeta8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-beta1 activation and immunosuppression by Tregs. Structural basis of latent TGF-beta1 presentation and activation by GARP on human regulatory T cells.,Lienart S, Merceron R, Vanderaa C, Lambert F, Colau D, Stockis J, van der Woning B, De Haard H, Saunders M, Coulie PG, Savvides SN, Lucas S Science. 2018 Oct 25. pii: science.aau2909. doi: 10.1126/science.aau2909. PMID:30361387 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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