Tail engagement of arrestin at the glucagon receptor

doi:10.1038/s41586-023-06420-x

	Tail engagement of arrestin at the glucagon receptor
	Chen, Kun 1,2; Zhang, Chenhui 1,2; Lin, Shuling 1; Yan, Xinyu 3; Cai, Heng 4; Yi, Cuiying 1; Ma, Limin 1; Chu, Xiaojing 1; Liu, Yuchen 1,2; Zhu, Ya 5; Han, Shuo 1,2,4; Zhao, Qiang 1,2,3,6; Wu, Beili1,2,4,7
	2023-08-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
发表状态	已发表
DOI	10.1038/s41586-023-06420-x
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.
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收录类别	SCI
语种	英语
资助项目	National Science Foundation of China["82121005","JCYJ-SHFY-2021-008"] ; National Key Ramp;D Program of China[2022YFA1302900] ; CAS Strategic Priority Research Program[XDB37030100] ; null[31825010]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001049610700014
出版者	NATURE PORTFOLIO
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/325754
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_吴蓓丽组
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
通讯作者单位	生命科学与技术学院
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.
APA	Chen, Kun.,Zhang, Chenhui.,Lin, Shuling.,Yan, Xinyu.,Cai, Heng.,...&Wu, Beili.(2023).Tail engagement of arrestin at the glucagon receptor.NATURE.
MLA	Chen, Kun,et al."Tail engagement of arrestin at the glucagon receptor".NATURE (2023).