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Structure paper

TitleSpecificity of TGF-β1 signal designated by LRRC33 and integrin αβ.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 4988, Year 2022
Publish dateAug 25, 2022
AuthorsZelin 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 AbstractMyeloid 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 linksNat Commun / PubMed:36008481 / PubMed Central
MethodsEM (single particle)
Resolution3.24 - 5.19 Å
Structure data

EMDB-33571, PDB-7y1r:
Human L-TGF-beta1 in complex with the anchor protein LRRC33
Method: EM (single particle) / Resolution: 4.01 Å

EMDB-33572, PDB-7y1t:
Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-33573: Complex of integrin alphaV/beta8, L-TGF-beta1, and LRRC33 at a ratio of 2:2:1
Method: EM (single particle) / Resolution: 5.19 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

ChemComp-MN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / NRROS / anchor protein

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