Melody G Campbell1, Anthony Cormier2, Saburo Ito2, Robert I Seed2, Andrew J Bondesson2, Jianlong Lou3, James D Marks3, Jody L Baron4, Yifan Cheng5, Stephen L Nishimura6. 1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. 2. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. 3. Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA. 4. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. 5. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: yifan.cheng@ucsf.edu. 6. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA. Electronic address: stephen.nishimura@ucsf.edu.
Abstract
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.
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 stn class="Species">rategy 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.
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