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Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4.
Xiao, Peng; Guo, Shengchao; Wen, Xin; He, Qing-Tao; Lin, Hui; Huang, Shen-Ming; Gou, Lu; Zhang, Chao; Yang, Zhao; Zhong, Ya-Ni; Yang, Chuan-Cheng; Li, Yu; Gong, Zheng; Tao, Xiao-Na; Yang, Zhi-Shuai; Lu, Yan; Li, Shao-Long; He, Jun-Yan; Wang, Chuanxin; Zhang, Lei; Kong, Liangliang; Sun, Jin-Peng; Yu, Xiao.
Afiliación
  • Xiao P; Department of Clinical Laboratory, The Second Hospital, and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • Guo S; National Facility for Protein Science in Shanghai, Zhangjiang Laboratory, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 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; 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.
  • Gou L; 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.
  • Zhang C; 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.
  • Yang Z; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China.
  • Zhong YN; 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.
  • 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; 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.
  • Gong 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.
  • 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; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China.
  • Lu Y; 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.
  • 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; 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.
  • Zhang L; 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.
  • Kong L; 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.
  • Sun JP; Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong Univerisity, Jinan, China.
  • Yu X; 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.
Nature ; 604(7907): 771-778, 2022 04.
Article en En | MEDLINE | ID: mdl-35418677
Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and ß subunits1-3. A tethered agonism mediated by the 'Stachel sequence' of the ß subunit has been proposed to have central roles in aGPCR activation4-6. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the Gs heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-ß-Gs complex and the ADGRG4-ß-Gs complex (in which ß indicates the ß 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-Gs). The Stachel sequences of both ADGRG2-ß and ADGRG4-ß 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-ß or ADGRG4-ß extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-Gs 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-ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Receptores Acoplados a Proteínas G Límite: Humans Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido