Dynamic allostery drives autocrine and paracrine TGF-ß signaling.

ABSTRACT

TGF-ß, essential for development and immunity, is expressed as a latent complex (L-TGF-ß) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvß8 activates L-TGF-ß1/GARP. The dogma is that mature TGF-ß must physically dissociate from L-TGF-ß1 for signaling to occur. Our previous studies discovered that αvß8-mediated TGF-ß autocrine signaling can occur without TGF-ß1 release from its latent form. Here, we show that mice engineered to express TGF-ß1 that cannot release from L-TGF-ß1 survive without early lethal tissue inflammation, unlike those with TGF-ß1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-ß1 signaling without release where αvß8 binding redistributes the intrinsic flexibility of L-TGF-ß1 to expose TGF-ß1 to its receptors. Dynamic allostery explains the TGF-ß3 latency/activation mechanism and why TGF-ß3 functions distinctly from TGF-ß1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.