Dynamic allostery drives autocrine and paracrine TGF-β signaling
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.
Authors
- Melody G. Campbell (ORCID: https://orcid.org/0000-0003-1909-5751)
- Yifan Cheng (ORCID: https://orcid.org/0000-0001-9535-0369)
- Jianlong Lou (ORCID: https://orcid.org/0000-0001-6455-692X)
- Saburo Ito (ORCID: https://orcid.org/0000-0001-6619-4950)
- Jody L. Baron (ORCID: https://orcid.org/0000-0003-2799-9099)
- James D. Marks (ORCID: https://orcid.org/0000-0003-0562-3517)
- Stephen L. Nishimura (ORCID: https://orcid.org/0000-0003-2312-4113)
- Nicholas D. Carey (ORCID: https://orcid.org/0000-0001-5859-7549)
- Mingliang Jin (ORCID: https://orcid.org/0000-0003-4961-7143)
- Stephanie A. Wankowicz (ORCID: https://orcid.org/0000-0002-4225-7459)
- Anthony Cormier (ORCID: https://orcid.org/0000-0002-2848-9536)
- Phu K. Tang
- Pilar Cossio (ORCID: https://orcid.org/0000-0002-5404-9948)
- Jillian M. Jespersen (ORCID: https://orcid.org/0000-0002-8231-6978)
- Zanlin Yu (ORCID: https://orcid.org/0000-0001-8381-8788)
- Robert Seed (ORCID: https://orcid.org/0000-0002-7588-9903)
- Weihua Wen
- Tiffany Shing
- Guoqing Cai
- Li Ping Wang (ORCID: https://orcid.org/0000-0001-6893-3809)
Institutions
- University of California, San Francisco (US)
- University of California San Francisco Medical Center (US)
- Flatiron Health (United States) (US)
- Flatiron Institute (US)
Publication Details
- Journal
- Cell
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1016/j.cell.2024.08.036
- Citations
- 40
- Primary Topic
- Cell Adhesion Molecules Research
- Type
- article
- Field-Weighted Citation Impact
- 15.31
Funders
- Howard Hughes Medical Institute
- Cancer Research Coordinating Committee
- National Institutes of Health
- University of California, San Francisco