Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3

Yuxuan Peng, Akiko Fujimura, Jinta Asami, Zhikuan Zhang, Toshiyuki Shimizu () and Umeharu Ohto ()
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Yuxuan Peng: The University of Tokyo
Akiko Fujimura: The University of Tokyo
Jinta Asami: The University of Tokyo
Zhikuan Zhang: The University of Tokyo
Toshiyuki Shimizu: The University of Tokyo
Umeharu Ohto: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64129-z

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