National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
U54HL119893
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL134183
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL113032
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
S10OD020054
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01GM098672
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
P41CA196276
米国
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
S10OD021741
米国
引用
ジャーナル: Cell / 年: 2020 タイトル: Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β. 著者: 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 / 要旨: 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. ...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.