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Integrin 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. Copyright © 2020 Elsevier Inc. All rights reserved.

Citation

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 Nishimura. Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β. Cell. 2020 Feb 06;180(3):490-501.e16

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PMID: 31955848

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