9KB8
Cryo-EM structure of LGR4-RSPO2-ZNRF3 complex (1:1:2)
Summary for 9KB8
| Entry DOI | 10.2210/pdb9kb8/pdb |
| EMDB information | 62220 |
| Descriptor | E3 ubiquitin-protein ligase ZNRF3, Leucine-rich repeat-containing G-protein coupled receptor 4, R-spondin-2, ... (4 entities in total) |
| Functional Keywords | wnt signal, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 164986.76 |
| Authors | Peng, Y.,Fujimura, A.,Asami, J.,Zhang, Z.,Shimizu, T.,Ohto, U. (deposition date: 2024-10-30, release date: 2025-10-15) |
| Primary citation | Peng, Y.,Fujimura, A.,Asami, J.,Zhang, Z.,Shimizu, T.,Ohto, U. Structural insights into Wnt/ beta-catenin signaling regulation by LGR4, R-spondin, and ZNRF3. Nat Commun, 16:8337-8337, 2025 Cited by PubMed Abstract: Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) plays a critical role in regulating the wingless-related integration site (Wnt) signaling pathway and is essential for organ development and carcinogenesis. LGR4, along with its ligand R-spondin (RSPO), potentiates Wnt/β-catenin signaling by recruiting its signaling suppressor, E3 ligase Zinc and Ring Finger 3 (ZNRF3), and inducing its membrane clearance. However, detailed mechanisms underlying this process remain unknown. In this study, we present the cryo-electron microscopy structures of human LGR4, the LGR4-RSPO2 and LGR4-RSPO2-ZNRF3 complexes. Upon RSPO2 binding, LGR4 undergoes no significant conformational changes in its transmembrane and extracellular domain structures or their relative orientations. LGR4, RSPO2, and ZNRF3 assemble into a 2:2:2 complex with the ZNRF3 dimer enclosed at the center. This ternary arrangement and forced dimerization of ZNRF3 likely underpin how LGR4 and RSPO2 potentiate Wnt/β-catenin signaling by sequestering ZNRF3 from Wnt receptors and facilitating its auto-inactivation. This study provides a structural basis for understanding the regulatory mechanism of Wnt/β-catenin signaling through the LGR4-RSPO2-ZNRF3 pathway and may offer opportunities for future drug development targeting this axis. PubMed: 41034211DOI: 10.1038/s41467-025-64129-z PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.25 Å) |
Structure validation
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