Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling

Lu Wang, Fangzheng Hu, Qianqian Cui, Huarui Qiao, Lingyun Li, Tengjie Geng, Yuying Li, Zengchao Sun, Siyu Zhou, Zhongyun Lan, Shaojue Guo, Ying Hu, Jiqiu Wang, Qilun Yang, Zenan Wang (), Yuanyuan Dai () and Yong Geng ()
Additional contact information
Lu Wang: Chinese Academy of Sciences
Fangzheng Hu: Chinese Academy of Sciences
Qianqian Cui: Chinese Academy of Sciences
Huarui Qiao: Chinese Academy of Sciences
Lingyun Li: Chinese Academy of Sciences
Tengjie Geng: Chinese Academy of Sciences
Yuying Li: Chinese Academy of Sciences
Zengchao Sun: Chinese Academy of Sciences
Siyu Zhou: Chinese Academy of Sciences
Zhongyun Lan: Chinese Academy of Sciences
Shaojue Guo: Chinese Academy of Sciences
Ying Hu: Chinese Academy of Sciences
Jiqiu Wang: Shanghai Jiao Tong University School of Medicine
Qilun Yang: Shanghai Kailuo Biotechnology Co. Ltd
Zenan Wang: Chinese Academy of Sciences
Yuanyuan Dai: Chinese Academy of Medical Sciences and Peking Union Medical College
Yong Geng: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract WNT/β-catenin signaling plays key roles in development and cancer1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling3–5. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane helices (TM helices). This specific assembly promotes a stable complex, facilitating LGR4-induced endocytosis of ZNRF3. In contrast, the active dimeric ZNRF3, bound by a single LGR4, adopts a coiled-coil TM helices conformation and dimerization of RING domains. Our findings unveil how LGR4 content mediates diverse assemblies, leading to conformational rearrangements in ZNRF3 to regulate WNT/β-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.

Date: 2025
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DOI: 10.1038/s41467-024-55431-3

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