Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.

Autor: Xiao P; Department of Clinical Laboratory, The Second Hospital, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.; National Facility for Protein Science in Shanghai, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Guo S; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Wen X; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., He QT; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Lin H; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Huang SM; State Key Laboratory for Strength and Vibration of Mechanical Structures, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an, China.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China., Gou L; State Key Laboratory for Strength and Vibration of Mechanical Structures, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an, China., Zhang C; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Yang Z; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Zhong YN; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Yang CC; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Li Y; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China., Gong Z; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Tao XN; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Yang ZS; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Lu Y; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Li SL; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., He JY; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Wang C; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong Univerisity, Jinan, China., Zhang L; State Key Laboratory for Strength and Vibration of Mechanical Structures, MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an, China. zhangleio@mail.xjtu.edu.cn., Kong L; National Facility for Protein Science in Shanghai, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China. kongliangliang@sari.ac.cn., Sun JP; Department of Clinical Laboratory, The Second Hospital, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China. sunjinpeng@sdu.edu.cn.; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn., Yu X; Key Laboratory of Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. yuxiao@sdu.edu.cn.; Center for Reproductive Medicine, and Key Laboratory of Reproductive Endocrinology, Ministry of Education, Shandong University, Jinan, China. yuxiao@sdu.edu.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Apr; Vol. 604 (7907), pp. 771-778. Date of Electronic Publication: 2022 Apr 13.
DOI: 10.1038/s41586-022-04590-8
Abstrakt: Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and β subunits 1-3 . A tethered agonism mediated by the 'Stachel sequence' of the β subunit has been proposed to have central roles in aGPCR activation 4-6 . Here we present three cryo-electron microscopy structures of aGPCRs coupled to the G s heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-β-G s complex and the ADGRG4-β-G s complex (in which β indicates the β subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-G s ). The Stachel sequences of both ADGRG2-β and ADGRG4-β assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-β or ADGRG4-β extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-G s complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-β structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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