8fxv
From Proteopedia
Crystal structure of human proTGF-beta2 in complex with Nb18
Structural highlights
DiseaseTGFB2_HUMAN Note=A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9. Defects in TGFB2 are the cause of Loeys-Dietz syndrome 4 (LDS4) [MIM:614816. An aortic aneurysm syndrome with widespread systemic involvement. LDS4 is characterized by arterial tortuosity, aortic dissection, intracranial aneurysm and subarachnoid hemorrhage, hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arachnodactyly, scoliosis, foot deformities, dural ectasia, joint hyperflexibility, and thin skin with easy bruising and striae.[1] FunctionTGFB2_HUMAN TGF-beta 2 has suppressive effects on interleukin-2 dependent T-cell growth. Publication Abstract from PubMedActivation of latent transforming growth factor (TGF)-beta2 is incompletely understood. Unlike TGF-beta1 and beta3, the TGF-beta2 prodomain lacks a seven-residue RGDLXX (L/I) integrin-recognition motif and is thought not to be activated by integrins. Here, we report the surprising finding that TGF-beta2 contains a related but divergent 13-residue integrin-recognition motif (YTSGDQKTIKSTR) that specializes it for activation by integrin alphaVbeta6 but not alphaVbeta8. Both classes of motifs compete for the same binding site in alphaVbeta6. Multiple changes in the longer motif underlie its specificity. ProTGF-beta2 structures define interesting differences from proTGF-beta1 and the structural context for activation by alphaVbeta6. Some integrin-independent activation is also seen for proTGF-beta2 and even more so for proTGF-beta3. Our findings have important implications for therapeutics to alphaVbeta6 in clinical trials for fibrosis, in which inhibition of TGF-beta2 activation has not been anticipated. A specialized integrin-binding motif enables proTGF-beta2 activation by integrin alphaVbeta6 but not alphaVbeta8.,Le VQ, Zhao B, Ramesh S, Toohey C, DeCosta A, Mintseris J, Liu X, Gygi S, Springer TA Proc Natl Acad Sci U S A. 2023 Jun 13;120(24):e2304874120. doi: , 10.1073/pnas.2304874120. Epub 2023 Jun 6. PMID:37279271[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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