Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling

Huarui Qiao, Fangzheng Hu, Yiang Wang, Lu Wang, Siyu Zhou, Shaojue Guo, Yiwen Xu, Jianfeng Xu, Qianqian Cui, Qilun Yang, H. Eric Xu (), Jianwei Zhu () and Yong Geng ()
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Huarui Qiao: Shanghai Jiao Tong University
Fangzheng Hu: Shanghai Jiao Tong University
Yiang Wang: Chinese Academy of Sciences
Lu Wang: Chinese Academy of Sciences
Siyu Zhou: Chinese Academy of Sciences
Shaojue Guo: Chinese Academy of Sciences
Yiwen Xu: Chinese Academy of Sciences
Jianfeng Xu: Shanghai Ocean University
Qianqian Cui: Chinese Academy of Sciences
Qilun Yang: Shanghai Kailuo Biotechnology Co., Ltd.
H. Eric Xu: Chinese Academy of Sciences
Jianwei Zhu: Shanghai Jiao Tong University
Yong Geng: Shanghai Jiao Tong University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract The Wnt/β-catenin pathway requires precise regulation for proper development and tissue homeostasis, yet the structural mechanisms enabling its fine-tuned control remain incompletely understood. Here, we reveal how LGR4 achieves differential signaling outcomes through distinct recognition of two key modulators: Norrin and R-spondins (RSPOs). Using cryo-electron microscopy, we determined the structure of full-length LGR4 bound to Norrin in a 2:2 stoichiometry, revealing a molecular bridging mechanism where Norrin dimer connect two LGR4 protomers in a spatial arrangement fundamentally distinct from the LGR4-RSPO2-ZNRF3 complex. Notably, Norrin binding to LGR4 sterically hinders simultaneous interaction with the Frizzled4 receptor, establishing a regulatory checkpoint in Wnt signaling. The partially overlapping binding sites for Norrin and RSPOs on LGR4 enable mutually exclusive interactions that drive distinct signaling outcomes. Disease-linked mutations map to distinct functional regions: those disrupting LGR4 interaction are associated with familial exudative vitreoretinopathy (FEVR), while others impairing Frizzled4 binding are linked to Norrie disease. Furthermore, we developed a high-affinity nanobody that blocks both Norrin and RSPO binding to LGR4, providing a potential tool for therapeutic intervention. These findings elucidate the structural basis of LGR4’s dual signaling roles and lay the groundwork for therapeutic strategies targeting Wnt-related diseases.

Date: 2025
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DOI: 10.1038/s41467-025-61545-z

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