| First Author | Jin M | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 22 | Pages | 6200-6219.e23 |
| PubMed ID | 39288764 | Mgi Jnum | J:359199 |
| Mgi Id | MGI:7779295 | Doi | 10.1016/j.cell.2024.08.036 |
| Citation | Jin M, et al. (2024) Dynamic allostery drives autocrine and paracrine TGF-beta signaling. Cell 187(22):6200-6219.e23 |
| abstractText | TGF-beta, essential for development and immunity, is expressed as a latent complex (L-TGF-beta) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin alphavbeta8 activates L-TGF-beta1/GARP. The dogma is that mature TGF-beta must physically dissociate from L-TGF-beta1 for signaling to occur. Our previous studies discovered that alphavbeta8-mediated TGF-beta autocrine signaling can occur without TGF-beta1 release from its latent form. Here, we show that mice engineered to express TGF-beta1 that cannot release from L-TGF-beta1 survive without early lethal tissue inflammation, unlike those with TGF-beta1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-beta1 signaling without release where alphavbeta8 binding redistributes the intrinsic flexibility of L-TGF-beta1 to expose TGF-beta1 to its receptors. Dynamic allostery explains the TGF-beta3 latency/activation mechanism and why TGF-beta3 functions distinctly from TGF-beta1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems. |
