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Title | Specificity of TGF-β1 signal designated by LRRC33 and integrin αβ. |
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Journal, issue, pages | Nat Commun, Vol. 13, Issue 1, Page 4988, Year 2022 |
Publish date | Aug 25, 2022 |
Authors | Zelin Duan / Xuezhen Lin / Lixia Wang / Qiuxin Zhen / Yuefeng Jiang / Chuxin Chen / Jing Yang / Chia-Hsueh Lee / Yan Qin / Ying Li / Bo Zhao / Jianchuan Wang / Zhe Zhang / |
PubMed Abstract | Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ activates extracellular L-TGF-β1 to trigger ...Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ 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 αβ/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 αβ 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 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 αβ. |
External links | Nat Commun / PubMed:36008481 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.24 - 5.19 Å |
Structure data | EMDB-33571, PDB-7y1r: EMDB-33572, PDB-7y1t: EMDB-33573: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1 |
Chemicals | ChemComp-NAG: ChemComp-CA: ChemComp-MN: |
Source |
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Keywords | SIGNALING PROTEIN / NRROS / anchor protein |