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Publication Abstract from PubMed

Myeloid lineage cells present the latent form of transforming growth factor-beta1 (L-TGF-beta1) to the membrane using an anchor protein LRRC33. Integrin alphaVbeta8 activates extracellular L-TGF-beta1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-beta1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-beta1/LRRC33 and integrin alphaVbeta8/L-TGF-beta1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-beta1 but not the -beta2 or -beta3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin alphaVbeta8 and L-TGF-beta1, which shows higher avidity and more efficient L-TGF-beta1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit beta8 determines its exquisite affinity to L-TGF-beta1. Together, our findings provide important insights into the specificity of TGF-beta1 signaling achieved by LRRC33 and integrin alphaVbeta8.

Specificity of TGF-beta1 signal designated by LRRC33 and integrin alphaVbeta8.,Duan Z, Lin X, Wang L, Zhen Q, Jiang Y, Chen C, Yang J, Lee CH, Qin Y, Li Y, Zhao B, Wang J, Zhang Z Nat Commun. 2022 Aug 25;13(1):4988. doi: 10.1038/s41467-022-32655-9. PMID:36008481^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.