6UJA

Integrin alpha-v beta-8 in complex with pro-TGF-beta1

Summary for 6UJA

• Entry DOI: 10.2210/pdb6uja/pdb
• EMDB information: 20794 20795 20796 20797 20798 20799 20800 20801 20802 21125
• Descriptor: Integrin alpha-V, Integrin beta-8, Transforming growth factor beta-1 proprotein, ... (8 entities in total)
• Functional Keywords: glycoprotein, adhesion, signaling, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 239183.35

Authors

Campbell, M.G.,Cormier, A.,Cheng, Y.,Nishimura, S.L. (deposition date: 2019-10-02, release date: 2020-02-05, Last modification date: 2024-10-16)

Primary citation

Campbell, M.G.,Cormier, A.,Ito, S.,Seed, R.I.,Bondesson, A.J.,Lou, J.,Marks, J.D.,Baron, J.L.,Cheng, Y.,Nishimura, S.L.
Cryo-EM Reveals Integrin-Mediated TGF-beta Activation without Release from Latent TGF-beta.
Cell, 180:490-, 2020

PubMed 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.

PubMed: 31955848
DOI: 10.1016/j.cell.2019.12.030

Experimental method

ELECTRON MICROSCOPY (3.3 Å)