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

文献类型：期刊论文

作者Wang, Lu8; Hu, Fangzheng8; Cui, Qianqian8; Qiao, Huarui8; Li, Lingyun7,8; Geng, Tengjie8; Li, Yuying8; Sun, Zengchao8; Zhou, Siyu8; Lan, Zhongyun8
刊名NATURE COMMUNICATIONS
出版日期2025-01-03
卷号16期号:1页码:13
DOI10.1038/s41467-024-55431-3
英文摘要WNT/beta-catenin signaling plays key roles in development and cancer1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/beta-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/beta-catenin signaling3, 4-5. 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/beta-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.
WOS关键词R-SPONDIN RECOGNITION ; CRYSTAL-STRUCTURE ; E3 LIGASE ; UBIQUITIN LIGASES ; WNT RECEPTORS ; IONIC LOCK ; LGR5 ; DIMERIZATION ; ACTIVATION ; RNF43
资助项目National Natural Science Foundation of China (National Science Foundation of China) ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SQ2023YFB3200066] ; National Key Research and Development Program of China[18JC1415400] ; Science and Technology Commission of Shanghai Municipality[31670743] ; Science and Technology Commission of Shanghai Municipality[U24A20675] ; Science and Technology Commission of Shanghai Municipality[62273329] ; National Natural Science Foundation of China
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001402050600015
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/315938]  
专题新药研究国家重点实验室
通讯作者Wang, Zenan; Dai, Yuanyuan; Geng, Yong
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.Chinese Acad Med Sci, Natl Canc Ctr, Natl Clin Res Ctr Canc, Canc Hosp, Langfang Campus, Langfang, Peoples R China
3.Chinese Acad Med Sci & Peking Union Med Coll, Canc Hosp, Dept Pharm, Natl Clin Res Ctr Canc,Natl Canc Ctr, Beijing, Peoples R China
4.Shanghai Kailuo Biotechnol Co Ltd, Shanghai, Peoples R China
5.Natl Hlth Commiss PR China, Key Lab Endocrine & Metab Dis, Shanghai Natl Clin Res Ctr Metab Dis, Shanghai Natl Ctr Translat Med, Shanghai, Peoples R China
6.Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Endocrine & Metab Dis, Dept Endocrine & Metab Dis,Sch Med, Shanghai, Peoples R China
7.Chinese Acad Sci, Shenzhen Inst Adv Technol, Ctr Cognit Technol, Shenzhen, Guangdong, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Lu,Hu, Fangzheng,Cui, Qianqian,et al. Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling[J]. NATURE COMMUNICATIONS,2025,16(1):13.
APA Wang, Lu.,Hu, Fangzheng.,Cui, Qianqian.,Qiao, Huarui.,Li, Lingyun.,...&Geng, Yong.(2025).Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.NATURE COMMUNICATIONS,16(1),13.
MLA Wang, Lu,et al."Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling".NATURE COMMUNICATIONS 16.1(2025):13.

入库方式： OAI收割

来源：上海药物研究所

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