Specificity of TGF-ß1 signal designated by LRRC33 and integrin αVß8.

ABSTRACT

Myeloid lineage cells present the latent form of transforming growth factor-ß1 (L-TGF-ß1) to the membrane using an anchor protein LRRC33. Integrin αVß8 activates extracellular L-TGF-ß1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-ß1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-ß1/LRRC33 and integrin αVß8/L-TGF-ß1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-ß1 but not the -ß2 or -ß3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 22 binding mode of integrin αVß8 and L-TGF-ß1, which shows higher avidity and more efficient L-TGF-ß1 activation than previously reported 12 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit ß8 determines its exquisite affinity to L-TGF-ß1. Together, our findings provide important insights into the specificity of TGF-ß1 signaling achieved by LRRC33 and integrin αVß8.