| 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
|
| Resource |
| DNA material |
NRCD human cDNA clone ARiS118G09 (HKR247353) |
