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

ABSTRACT: Integrin ?v?8 binds with exquisite specificity to latent transforming growth factor-? (L-TGF-?). This binding is essential for activating L-TGF-? presented by a variety of cell types. Inhibiting ?v?8-mediated TGF-? 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 ?v?8 ectodomain and its intact natural ligand, L-TGF-?, as well as two different inhibitory antibody fragments to understand the structural underpinnings of ?v?8 binding specificity and TGF-? activation. Our studies reveal a mechanism of TGF-? activation where mature TGF-? signals within the confines of L-TGF-? and the release and diffusion of TGF-? are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit ?v?8-mediated L-TGF-? activation.

SUBMITTER: Campbell MG 

PROVIDER: S-EPMC7238552 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature