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Nat Struct Mol Biol. 2019 Dec;26(12):1123-1131. doi: 10.1038/s41594-019-0330-y. Epub 2019 Nov 18.

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

Author information

1
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
2
Department of Biochemistry, Duke University Medical Center, Durham, NC, USA.
3
Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA.
4
Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
5
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
6
Center for Host-Pathogen Interaction, Columbia University Irving Medical Center, New York, NY, USA.
7
Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
8
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
9
The Irving Center for Clinical and Translational Research, Columbia University Irving Medical Center, New York, NY, USA.
10
Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
11
Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA.
12
The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
13
Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
14
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
15
Department of Structural Biology, Stanford University, Stanford, CA, USA.
16
Structural Biology Brussels, Vrije Universiteit Brussels, Brussels, Belgium.
17
Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, Brussels, Belgium.
18
School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China.
19
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
20
Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA. adesgeorges@gc.cuny.edu.
21
Department of Chemistry and Biochemistry, City College of New York, New York, NY, USA. adesgeorges@gc.cuny.edu.
22
Biochemistry and Chemistry PhD Programs, Graduate Center, City University of New York, New York, NY, USA. adesgeorges@gc.cuny.edu.
23
Department of Medicine, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.
24
Department of Biochemistry, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.
25
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA. lefko001@receptor-biol.duke.edu.

Abstract

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.

PMID:
31740855
DOI:
10.1038/s41594-019-0330-y

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