Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1
文献类型：期刊论文
| 作者 | Qu, Xiangli1,2; Qiu, Na1,2; Wang, Mu1,3; Zhang, Bingjie4; Du, Juan5; Zhong, Zhiwei6; Xu, Wei1,2; Chu, Xiaojing1; Ma, Limin1; Yi, Cuiying1 |
| 刊名 | NATURE
 |
| 出版日期 | 2022-04-13 |
| 页码 | 24 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-022-04580-w |
| 通讯作者 | Shui, Wenqing(shuiwq@shanghaitech.edu.cn) ; Zhao, Qiang(zhaoq@simm.ac.cn) ; Wu, Beili(beiliwu@simm.ac.cn) |
| 英文摘要 | 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. |
| WOS关键词 | PROTEIN-COUPLED RECEPTORS ; CNS ANGIOGENESIS ; IDENTIFICATION ; ACTIVATION ; COMPLEX ; MOTIFS ; GPR110 |
| 资助项目 | National Science Foundation of China[31825010] ; National Science Foundation of China[82121005] ; National Science Foundation of China[32171439] ; National Science Foundation of China[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 |
| 语种 | 英语 |
| 出版者 | NATURE PORTFOLIO |
| WOS记录号 | WOS:000782392700004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/299731]  |
| 专题 | 新药研究国家重点实验室 |
| 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 |
| 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,2022:24. |
| 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,24. |
| MLA | Qu, Xiangli,et al."Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1".NATURE (2022):24. |
入库方式： OAI收割
来源：上海药物研究所
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