Structural basis for the tethered peptide activation of adhesion GPCRs.

Autor: Ping YQ; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China., Xiao P; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China., Yang F; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.; Advanced Medical Research Institute, Shandong University, Jinan, China., Zhao RJ; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Guo SC; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Yan X; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Wu X; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Zhang C; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Lu Y; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Zhao F; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Zhou F; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Xi YT; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, China., Yin W; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Liu FZ; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., He DF; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.; Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China., Zhang DL; School of Pharmacy, Binzhou Medical University, Yantai, China., Zhu ZL; School of Life Sciences, University of Science and Technology of China, Hefei, China., Jiang Y; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China., Du L; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China., Feng SQ; Advanced Medical Research Institute, Shandong University, Jinan, China., Schöneberg T; Molecular Biochemistry, Medical Faculty, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany., Liebscher I; Molecular Biochemistry, Medical Faculty, Rudolf Schönheimer Institute of Biochemistry, Leipzig, Germany. Ines.Liebscher@medizin.uni-leipzig.de., Xu HE; CAS Key Laboratory of Receptor Research, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn., Sun JP; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn.; Key Laboratory of Molecular Cardiovascular Science of the Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China. sunjinpeng@sdu.edu.cn.; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn.; Advanced Medical Research Institute, Shandong University, Jinan, China. sunjinpeng@sdu.edu.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Apr; Vol. 604 (7907), pp. 763-770. Date of Electronic Publication: 2022 Apr 13.
DOI: 10.1038/s41586-022-04619-y
Abstrakt: Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes 1-6 . Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence 7-12 . Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G s : GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W 6.53 and the constitution of a hydrogen-bond network formed by Q 7.49 /Y 7.49 and the P 6.47 /V 6.47 φφG 6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G s coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G s -binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G s . Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G s coupling.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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