Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1
Qu, Xiangli1,2; Qiu, Na1,2; Wang, Mu1,3; Zhang, Bingjie4; Du, Juan5; Zhong, Zhiwei6; Xu, Wei1,2; Chu, Xiaojing1; Ma, Limin1; Yi, Cuiying1
2022
发表期刊NATURE
ISSN0028-0836
EISSN1476-4687
卷号604期号:7907页码:779-785
发表状态已发表
DOI10.1038/s41586-022-04580-w
摘要

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis(1-7). An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs(8,9), but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

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收录类别SCI ; SCIE
语种英语
资助项目National Science Foundation of China[31825010,82121005,32171439,31971362] ; National Key R&D Program of China[2018YFA0507000] ; CAS Strategic Priority Research Program[XDB37030100] ; Shanghai Pilot Program for Basic Research-Chinese Academy of Sciences, Shanghai Branch[JCYJ-SHFY-2021-008]
WOS研究方向Science & Technology - Other Topics
WOS类目Multidisciplinary Sciences
WOS记录号WOS:000782392700004
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/176016
专题iHuman研究所_PI研究组_水雯箐组
生命科学与技术学院_特聘教授组_吴蓓丽组
生命科学与技术学院_博士生
通讯作者Shui, Wenqing; Zhao, Qiang; Wu, Beili
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, iHuman Inst, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
7.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, 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
Qu, Xiangli,Qiu, Na,Wang, Mu,et al. Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1[J]. NATURE,2022,604(7907):779-785.
APA Qu, Xiangli.,Qiu, Na.,Wang, Mu.,Zhang, Bingjie.,Du, Juan.,...&Wu, Beili.(2022).Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.NATURE,604(7907),779-785.
MLA Qu, Xiangli,et al."Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1".NATURE 604.7907(2022):779-785.
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