2025-10-01 東京大学
LGR4/RSPO2/ZNRF3複合体によるWnt/β-カテニンシグナル伝達機構の調節メカニズム
<関連情報>
- https://www.k.u-tokyo.ac.jp/information/category/press/0027752.html
- https://www.nature.com/articles/s41467-025-64129-z
LGR4、R-スポンジン、ZNRF3によるWnt/β-カテニンシグナル伝達制御の構造的知見 Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3
Yuxuan Peng,Akiko Fujimura,Jinta Asami,Zhikuan Zhang,Toshiyuki Shimizu & Umeharu Ohto
Nature Communications Published:01 October 2025
DOI:https://doi.org/10.1038/s41467-025-64129-z
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.
