Dynamic allostery drives autocrine and paracrine TGF-β signaling.

Autor:	Jin M; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF), San Francisco, CA, USA., Seed RI; Department of Pathology, UCSF, San Francisco, CA, USA., Cai G; Department of Pathology, UCSF, San Francisco, CA, USA., Shing T; Department of Pathology, UCSF, San Francisco, CA, USA., Wang L; Department of Pathology, UCSF, San Francisco, CA, USA., Ito S; Department of Pathology, UCSF, San Francisco, CA, USA., Cormier A; Department of Pathology, UCSF, San Francisco, CA, USA., Wankowicz SA; Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA, USA., Jespersen JM; Department of Medicine and UCSF Liver Center, UCSF, San Francisco, CA, USA., Baron JL; Department of Medicine and UCSF Liver Center, UCSF, San Francisco, CA, USA., Carey ND; Department of Medicine and UCSF Liver Center, UCSF, San Francisco, CA, USA., Campbell MG; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF), San Francisco, CA, USA., Yu Z; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF), San Francisco, CA, USA., Tang PK; Center for Computational Mathematics, Flatiron Institute, New York, NY, USA., Cossio P; Center for Computational Mathematics, Flatiron Institute, New York, NY, USA; Center for Computational Biology, Flatiron Institute, New York, NY, USA., Wen W; Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, USA., Lou J; Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, USA., Marks J; Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, USA., Nishimura SL; Department of Pathology, UCSF, San Francisco, CA, USA. Electronic address: stephen.nishimura@ucsf.edu., Cheng Y; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF), San Francisco, CA, USA; Howard Hughes Medical Institute, UCSF, San Francisco, CA, USA. Electronic address: yifan.cheng@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Oct 31; Vol. 187 (22), pp. 6200-6219.e23. Date of Electronic Publication: 2024 Sep 16.
DOI:	10.1016/j.cell.2024.08.036
Abstrakt:	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. Competing Interests: Declaration of interests S.L.N. is on the scientific advisory board (SAB) of Corbus Pharmaceuticals, LLC. Y.C. is on the SABs of ShuiMu BioSciences Ltd. and Pamplona Therapeutics. A provisional patent has been filed by the Regents of the University of California. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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