9KB7

Cryo-EM structure of LGR4-RSPO2 complex

9KB7 の概要

• エントリーDOI: 10.2210/pdb9kb7/pdb
• EMDBエントリー: 62219
• 分子名称: Leucine-rich repeat-containing G-protein coupled receptor 4, R-spondin-2 (2 entities in total)
• 機能のキーワード: wnt signal, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 112325.76

構造登録者

Peng, Y.,Fujimura, A.,Asami, J.,Zhang, Z.,Shimizu, T.,Ohto, U. (登録日: 2024-10-30, 公開日: 2025-10-15)

主引用文献

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

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: 41034211
DOI: 10.1038/s41467-025-64129-z

実験手法

ELECTRON MICROSCOPY (3.97 Å)