GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.
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.
Thomsen, ARB; Plouffe, B; Cahill, TJ; Shukla, AK; Tarrasch, JT; Dosey, AM; Kahsai, AW; Strachan, RT; Pani, B; Mahoney, JP; Huang, L; Breton, B; Heydenreich, FM; Sunahara, RK; Skiniotis, G; Bouvier, M; Lefkowitz, RJ
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