8VSD

avb8/L-TGF-b1/GARP

Summary for 8VSD

• Entry DOI: 10.2210/pdb8vsd/pdb
• EMDB information: 43489 43492 43493 43494
• Descriptor: Transforming growth factor beta activator LRRC32, Integrin alpha-V heavy chain, Integrin beta-8, ... (9 entities in total)
• Functional Keywords: integrin, complex, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 252491.80

Authors

Jin, M.,Cheng, Y.,Nishimura, S.L. (deposition date: 2024-01-23, release date: 2024-09-11, Last modification date: 2024-11-13)

Primary citation

Jin, M.,Seed, R.I.,Cai, G.,Shing, T.,Wang, L.,Ito, S.,Cormier, A.,Wankowicz, S.A.,Jespersen, J.M.,Baron, J.L.,Carey, N.D.,Campbell, M.G.,Yu, Z.,Tang, P.K.,Cossio, P.,Wen, W.,Lou, J.,Marks, J.,Nishimura, S.L.,Cheng, Y.
Dynamic allostery drives autocrine and paracrine TGF-beta signaling.
Cell, 187:6200-6219.e23, 2024

PubMed Abstract: TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.

PubMed: 39288764
DOI: 10.1016/j.cell.2024.08.036

Experimental method

ELECTRON MICROSCOPY (3.2 Å)