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

Publication date: Available online 16 January 2020Source: CellAuthor(s): Melody G. Campbell, Anthony Cormier, Saburo Ito, Robert I. Seed, Andrew J. Bondesson, Jianlong Lou, James D. Marks, Jody L. Baron, Yifan Cheng, Stephen L. NishimuraSummaryIntegrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β 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 αvβ8 ectodomain and its intact natural ligand, L-TGF-β, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies reveal a mechanism of TGF-β activation where mature TGF-β signals within the confines of L-TGF-β and the release and diffusion of TGF-β are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation.Graphical Abstract
Source: Cell - Category: Cytology Source Type: research