Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling
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 o...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61545-z |
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| author | 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 |
| author_facet | 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 |
| author_sort | Huarui Qiao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1c2fee0b07cc47ec80a6e1040744fbda |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1c2fee0b07cc47ec80a6e1040744fbda2025-08-20T03:05:10ZengNature PortfolioNature Communications2041-17232025-07-0116111110.1038/s41467-025-61545-zDistinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signalingHuarui Qiao0Fangzheng Hu1Yiang Wang2Lu Wang3Siyu Zhou4Shaojue Guo5Yiwen Xu6Jianfeng Xu7Qianqian Cui8Qilun Yang9H. Eric Xu10Jianwei Zhu11Yong Geng12Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong UniversityEngineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Biopharmaceutics, College of Food Science and Technology, Shanghai Ocean UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesShanghai Kailuo Biotechnology Co., Ltd.State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesEngineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong UniversityEngineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong UniversityAbstract 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.https://doi.org/10.1038/s41467-025-61545-z |
| spellingShingle | 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 Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling Nature Communications |
| title | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling |
| title_full | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling |
| title_fullStr | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling |
| title_full_unstemmed | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling |
| title_short | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling |
| title_sort | distinct structural mechanisms of lgr4 modulation by norrin and rspos in wnt β catenin signaling |
| url | https://doi.org/10.1038/s41467-025-61545-z |
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