Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.

Autor: Nguyen AH; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA., Thomsen ARB; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA., Cahill TJ 3rd; Department of Medicine, Duke University Medical Center, Durham, NC, USA.; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA., Huang R; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA., Huang LY; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Marcink T; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.; Center for Host-Pathogen Interaction, Columbia University Irving Medical Center, New York, NY, USA., Clarke OB; Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.; The Irving Center for Clinical and Translational Research, Columbia University Irving Medical Center, New York, NY, USA., Heissel S; Proteomics Resource Center, The Rockefeller University, New York, NY, USA., Masoudi A; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Ben-Hail D; Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA., Samaan F; Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA., Dandey VP; The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA., Tan YZ; The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA., Hong C; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA., Mahoney JP; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.; Department of Structural Biology, Stanford University, Stanford, CA, USA., Triest S; Structural Biology Brussels, Vrije Universiteit Brussels, Brussels, Belgium.; Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, Brussels, Belgium., Little J 4th; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA., Chen X; School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China., Sunahara R; Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA., Steyaert J; Structural Biology Brussels, Vrije Universiteit Brussels, Brussels, Belgium., Molina H; Proteomics Resource Center, The Rockefeller University, New York, NY, USA., Yu Z; Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA., des Georges A; Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA. adesgeorges@gc.cuny.edu.; Department of Chemistry and Biochemistry, City College of New York, New York, NY, USA. adesgeorges@gc.cuny.edu.; Biochemistry and Chemistry PhD Programs, Graduate Center, City University of New York, New York, NY, USA. adesgeorges@gc.cuny.edu., Lefkowitz RJ; Department of Medicine, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.; Department of Biochemistry, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2019 Dec; Vol. 26 (12), pp. 1123-1131. Date of Electronic Publication: 2019 Nov 18.
DOI: 10.1038/s41594-019-0330-y
Abstrakt: 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 β 2 -adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β 2 V 2 R). 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.
Databáze: MEDLINE
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