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Cell. 2016 Aug 11;166(4):907-919. doi: 10.1016/j.cell.2016.07.004. Epub 2016 Aug 4.

GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.

Author information

1
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
2
Department of Biochemistry and Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada.
3
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
4
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
7
Department of Biochemistry and Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada. Electronic address: michel.bouvier@umontreal.ca.
8
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: lefko001@receptor-biol.duke.edu.

Abstract

Classically, G protein-coupled receptor (GPCR) stimulation promotes G protein signaling at the plasma membrane, followed by rapid β-arrestin-mediated desensitization and receptor internalization into endosomes. However, it has been demonstrated that some GPCRs activate G proteins from within internalized cellular compartments, resulting in sustained signaling. We have used a variety of biochemical, biophysical, and cell-based methods to demonstrate the existence, functionality, and architecture of internalized receptor complexes composed of a single GPCR, β-arrestin, and G protein. These super-complexes or "megaplexes" more readily form at receptors that interact strongly with β-arrestins via a C-terminal tail containing clusters of serine/threonine phosphorylation sites. Single-particle electron microscopy analysis of negative-stained purified megaplexes reveals that a single receptor simultaneously binds through its core region with G protein and through its phosphorylated C-terminal tail with β-arrestin. The formation of such megaplexes provides a potential physical basis for the newly appreciated sustained G protein signaling from internalized GPCRs.

PMID:
27499021
PMCID:
PMC5418658
DOI:
10.1016/j.cell.2016.07.004
[Indexed for MEDLINE]
Free PMC Article

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