Cargando…

Specificity of TGF-β1 signal designated by LRRC33 and integrin α(V)β(8)

Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α(V)β(8) activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 pre...

Descripción completa

Detalles Bibliográficos
Autores principales: Duan, Zelin, Lin, Xuezhen, Wang, Lixia, Zhen, Qiuxin, Jiang, Yuefeng, Chen, Chuxin, Yang, Jing, Lee, Chia-Hsueh, Qin, Yan, Li, Ying, Zhao, Bo, Wang, Jianchuan, Zhang, Zhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411592/
https://www.ncbi.nlm.nih.gov/pubmed/36008481
http://dx.doi.org/10.1038/s41467-022-32655-9
Descripción
Sumario:Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin α(V)β(8) activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin α(V)β(8)/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin α(V)β(8) and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β(8) determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin α(V)β(8).