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Tail engagement of arrestin at the glucagon receptor

文献类型：期刊论文

作者Chen, Kun1,2; Zhang, Chenhui1,2; Lin, Shuling1; Yan, Xinyu3; Cai, Heng4; Yi, Cuiying1; Ma, Limin1; Chu, Xiaojing1; Liu, Yuchen1,2; Zhu, Ya5
刊名NATURE
出版日期2023-08-09
页码21
ISSN号0028-0836
DOI10.1038/s41586-023-06420-x
通讯作者Zhao, Qiang(zhaoq@simm.ac.cn) ; Wu, Beili(beiliwu@simm.ac.cn)
英文摘要Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization(1,2). It has been proposed that the arrestin binds to the receptor in two different conformations, ' tail ' and ' core ', which were suggested to govern distinct processes of receptor signalling and trafficking(3,4). However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to ss-arrestin 1 (ss arr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of ss arr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating ss arr1 by forming extensive interactions with the central crest of ss arr1. The tail-binding pose is further defined by a close proximity between the ss arr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges ss arr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-ss arr governs ss arr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and ss arr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.
WOS关键词PROTEIN-COUPLED RECEPTORS ; CRYO-EM STRUCTURE ; BETA-ARRESTIN ; STRUCTURAL BASIS ; BIASED AGONISM ; GLP-1 RECEPTOR ; TRAFFICKING ; ENDOCYTOSIS ; COMPLEX ; PHOSPHORYLATION
资助项目National Science Foundation of China[82121005] ; National Science Foundation of China[JCYJ-SHFY-2021-008] ; National Key Ramp;D Program of China[2022YFA1302900] ; CAS Strategic Priority Research Program[XDB37030100] ; Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences, Shanghai ; [31825010]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:001049610700014
源URL[http://119.78.100.183/handle/2S10ELR8/307052]  
专题新药研究国家重点实验室
通讯作者Zhao, Qiang; Wu, Beili
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, State Key Lab Chem Biol, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
5.Lingang Lab, Shanghai, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Kun,Zhang, Chenhui,Lin, Shuling,et al. Tail engagement of arrestin at the glucagon receptor[J]. NATURE,2023:21.
APA Chen, Kun.,Zhang, Chenhui.,Lin, Shuling.,Yan, Xinyu.,Cai, Heng.,...&Wu, Beili.(2023).Tail engagement of arrestin at the glucagon receptor.NATURE,21.
MLA Chen, Kun,et al."Tail engagement of arrestin at the glucagon receptor".NATURE (2023):21.

入库方式： OAI收割

来源：上海药物研究所

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