+Search query
-Structure paper
Title | Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β. |
---|---|
Journal, issue, pages | Cell, Vol. 180, Issue 3, Page 490-501.e16, Year 2020 |
Publish date | Feb 6, 2020 |
Authors | 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 / |
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. ...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. |
External links | Cell / PubMed:31955848 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.87 - 3.6 Å |
Structure data | EMDB-20794: Integrin alpha-v beta-8 in complex with latent TGF-beta (Primary map: sharpened. Additional map: unsharpened.) EMDB-20795: Integrin alpha-v beta-8 in complex with Fabs C6D4 and 11D12v2 (Primary map: sharpened, focused refinement. Five additional maps.) EMDB-20796: Integrin alpha-v beta-8 in complex with Fabs C6-RGD3 and 11D12v2 (Primary map: sharpened, focused refinement. Five additional maps.) EMDB-20797: EMDB-20798: EMDB-20799: EMDB-20800: EMDB-20801: EMDB-20802: EMDB-21125: |
Chemicals | ChemComp-CA: ChemComp-NAG: ChemComp-MG: |
Source |
|
Keywords | SIGNALING PROTEIN / glycoprotein / adhesion / signaling / SIGNALING PROTEIN/IMMUNE SYSTEM / SIGNALING PROTEIN-IMMUNE SYSTEM complex |