Reference - Detail
| RRC ID | 85992 |
|---|---|
| Author | Peng Y, Fujimura A, Asami J, Zhang Z, Shimizu T, Ohto U. |
| Title | Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3. |
| Journal | Nat Commun |
| 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. |
| Volume | 16(1) |
| Pages | 8337 |
| Published | 2025-10-1 |
| DOI | 10.1038/s41467-025-64129-z |
| PII | 10.1038/s41467-025-64129-z |
| PMID | 41034211 |
| PMC | PMC12488874 |
| MeSH | Cryoelectron Microscopy HEK293 Cells Humans Models, Molecular Protein Binding R-Spondins Receptors, G-Protein-Coupled* / chemistry Receptors, G-Protein-Coupled* / genetics Receptors, G-Protein-Coupled* / metabolism Receptors, G-Protein-Coupled* / ultrastructure Thrombospondins* / chemistry Thrombospondins* / genetics Thrombospondins* / metabolism Ubiquitin-Protein Ligases* / chemistry Ubiquitin-Protein Ligases* / genetics Ubiquitin-Protein Ligases* / metabolism Ubiquitin-Protein Ligases* / ultrastructure Wnt Signaling Pathway* beta Catenin / metabolism |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 11 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | NRCD human cDNA clone ARiS118G09 (HKR247353) |