Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex
Copyright policy )Structure of an endosomal signaling GPCR–G protein–β-arrestin megacomplex
Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.
- University of California, San Diego United States
- National University of Singapore Singapore
- Vrije Universiteit Brussel Belgium
- Stanford University United States
- University of Michigan–Ann Arbor United States
Models, Molecular, Receptors, Vasopressin, Protein Conformation, 11 Medical and Health Sciences (for), Medical and Health Sciences, DESENSITIZATION, Receptors, G-Protein-Coupled, 34 Chemical sciences (for-2020), Models, Receptors, 31 Biological sciences (for-2020), CRYO-EM STRUCTURE, Animals (mesh), CRYSTAL-STRUCTURE, beta-2 (mesh), beta-Arrestins, Cryoelectron Microscopy (mesh), Developmental Biology (science-metrix), Humans (mesh), Generic health relevance (hrcs-hc), 03 Chemical Sciences (for), Biological Sciences, Endosomes (mesh), 06 Biological Sciences (for), Molecular (mesh), beta-Arrestins (mesh), Adrenergic, Life Sciences & Biomedicine, Vasopressin, Signal Transduction, Biochemistry & Molecular Biology, 570, Biophysics, PEPTIDE IDENTIFICATION, beta-2, Endosomes, Article, G-Protein-Coupled, COUPLED RECEPTOR, GTP-Binding Proteins, GLP-1 RECEPTOR, Animals, Humans, Vasopressin (mesh), 1.1 Normal biological development and functioning (hrcs-rac), Science & Technology, COMPLEX, 31 Biological Sciences (for-2020), Protein Conformation (mesh), Cryoelectron Microscopy, Molecular, Cell Biology, 540, 3101 Biochemistry and Cell Biology (for-2020), RESOLUTION, 32 Biomedical and clinical sciences (for-2020), Chemical Sciences, VISUALIZATION, Signal Transduction (mesh), G-Protein-Coupled (mesh), Cattle, Generic health relevance, Biophysics (science-metrix), Receptors, Adrenergic, beta-2, Cattle (mesh), GTP-Binding Proteins (mesh), Developmental Biology, BETA-ARRESTIN1
Models, Molecular, Receptors, Vasopressin, Protein Conformation, 11 Medical and Health Sciences (for), Medical and Health Sciences, DESENSITIZATION, Receptors, G-Protein-Coupled, 34 Chemical sciences (for-2020), Models, Receptors, 31 Biological sciences (for-2020), CRYO-EM STRUCTURE, Animals (mesh), CRYSTAL-STRUCTURE, beta-2 (mesh), beta-Arrestins, Cryoelectron Microscopy (mesh), Developmental Biology (science-metrix), Humans (mesh), Generic health relevance (hrcs-hc), 03 Chemical Sciences (for), Biological Sciences, Endosomes (mesh), 06 Biological Sciences (for), Molecular (mesh), beta-Arrestins (mesh), Adrenergic, Life Sciences & Biomedicine, Vasopressin, Signal Transduction, Biochemistry & Molecular Biology, 570, Biophysics, PEPTIDE IDENTIFICATION, beta-2, Endosomes, Article, G-Protein-Coupled, COUPLED RECEPTOR, GTP-Binding Proteins, GLP-1 RECEPTOR, Animals, Humans, Vasopressin (mesh), 1.1 Normal biological development and functioning (hrcs-rac), Science & Technology, COMPLEX, 31 Biological Sciences (for-2020), Protein Conformation (mesh), Cryoelectron Microscopy, Molecular, Cell Biology, 540, 3101 Biochemistry and Cell Biology (for-2020), RESOLUTION, 32 Biomedical and clinical sciences (for-2020), Chemical Sciences, VISUALIZATION, Signal Transduction (mesh), G-Protein-Coupled (mesh), Cattle, Generic health relevance, Biophysics (science-metrix), Receptors, Adrenergic, beta-2, Cattle (mesh), GTP-Binding Proteins (mesh), Developmental Biology, BETA-ARRESTIN1
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