7Y1R

Human L-TGF-beta1 in complex with the anchor protein LRRC33

Summary for 7Y1R

• Entry DOI: 10.2210/pdb7y1r/pdb
• EMDB information: 33571
• Descriptor: Transforming growth factor beta-1 proprotein, Transforming growth factor beta activator LRRC33, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: nrros, anchor protein, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 162214.74

Authors

Duan, Z.,Zhang, Z. (deposition date: 2022-06-08, release date: 2022-08-31, Last modification date: 2024-10-23)

Primary citation

Duan, Z.,Lin, X.,Wang, L.,Zhen, Q.,Jiang, Y.,Chen, C.,Yang, J.,Lee, C.H.,Qin, Y.,Li, Y.,Zhao, B.,Wang, J.,Zhang, Z.
Specificity of TGF-beta 1 signal designated by LRRC33 and integrin alpha V beta 8.
Nat Commun, 13:4988-4988, 2022

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 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.

PubMed: 36008481
DOI: 10.1038/s41467-022-32655-9

Experimental method

ELECTRON MICROSCOPY (4.01 Å)