Cryo-EM Reveals Integrin-Mediated TGF-ß Activation without Release from Latent TGF-ß.
Cell
; 180(3): 490-501.e16, 2020 02 06.
Article
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| MEDLINE
| ID: mdl-31955848
ABSTRACT
Integrin αvß8 binds with exquisite specificity to latent transforming growth factor-ß (L-TGF-ß). This binding is essential for activating L-TGF-ß presented by a variety of cell types. Inhibiting αvß8-mediated TGF-ß 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 αvß8 ectodomain and its intact natural ligand, L-TGF-ß, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvß8 binding specificity and TGF-ß activation. Our studies reveal a mechanism of TGF-ß activation where mature TGF-ß signals within the confines of L-TGF-ß and the release and diffusion of TGF-ß are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvß8-mediated L-TGF-ß activation.
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Base de datos:
MEDLINE
Asunto principal:
Integrinas
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Microscopía por Crioelectrón
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Factor de Crecimiento Transformador beta1
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Proteínas de Unión a TGF-beta Latente
Idioma:
En
Revista:
Cell
Año:
2020
Tipo del documento:
Article