EMD-20800

Single-particle
3.48 Å
EMD-20800 Deposition: 02/10/2019
Map released: 05/02/2020
Last modified: 02/12/2020
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-20800

Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation v (Primary map: sharpened. Additional map: unsharpened.)

EMD-20800

Single-particle
3.48 Å
EMD-20800 Deposition: 02/10/2019
Map released: 05/02/2020
Last modified: 02/12/2020
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Sus scrofa
Sample: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)
Raw data: EMPIAR-10343, EMPIAR-10344

Deposition Authors: Campbell MG, Cormier A, Cheng Y, Nishimura SL
Cryo-EM Reveals Integrin-Mediated TGF-beta Activation without Release from Latent TGF-beta.
Campbell MG , Cormier A , Ito S, Seed RI , Bondesson AJ, Lou J, Marks JD, Baron JL, Cheng Y , Nishimura SL
(2020) Cell , 180 , 490 - 501.e16
PUBMED: 31955848
DOI: doi:10.1016/j.cell.2019.12.030
ISSN: 1097-4172
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.