Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β

Integrin alpha v beta 8 binds with exquisite specificity to latent transforming growth factor-beta (L-TGF-beta). This binding is essential for activating L-TGF-beta presented by a variety of cell types. Inhibiting alpha v beta 8-mediated TGF-beta activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire alpha v beta 8 ectodomain and its intact natural ligand, L-TGF-beta, as well as two different inhibitory antibody fragments to understand the structural underpinnings of alpha v beta 8 binding specificity and TGF-beta activation. Our studies reveal a mechanism of TGF-beta activation where mature TGF-beta signals within the confines of L-TGF-beta and the release and diffusion of TGF-beta are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit alpha v beta 8-mediated L-TGF-beta activation.