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

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

Alex R B Thomsen 1, Bianca Plouffe 2, Thomas J Cahill 3rd 3, Arun K Shukla 1, Jeffrey T Tarrasch 4, Annie M Dosey 4, Alem W Kahsai 1, Ryan T Strachan 1, Biswaranjan Pani 1, Jacob P Mahoney 5, Liyin Huang 1, Billy Breton 2, Franziska M Heydenreich 2, Roger K Sunahara 6, Georgios Skiniotis 4, Michel Bouvier 7, Robert J Lefkowitz 8

PMID: 27499021 PMCID: PMC5418658 DOI: 10.1016/j.cell.2016.07.004

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.

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