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

Author

Listed:
  • Huarui Qiao

    (Shanghai Jiao Tong University
    Lingang Laboratory
    ShanghaiTech 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
    Shanghai Ocean University)

  • Yiwen Xu

    (Chinese Academy of Sciences
    Shanghai Ocean University)

  • 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
    Chinese Academy of Sciences)

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.

Suggested Citation

  • 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 & Yong Geng, 2025. "Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61545-z
    DOI: 10.1038/s41467-025-61545-z
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