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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)907-919
Number of pages13
JournalCell
Volume166
Issue number4
DOIs
StatePublished - Aug 11 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Thomsen, A. R. B., Plouffe, B., Cahill, T. J., Shukla, A. K., Tarrasch, J. T., Dosey, A. M., Kahsai, A. W., Strachan, R. T., Pani, B., Mahoney, J. P., Huang, L., Breton, B., Heydenreich, F. M., Sunahara, R. K., Skiniotis, G., Bouvier, M., & Lefkowitz, R. J. (2016). GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling. Cell, 166(4), 907-919. https://doi.org/10.1016/j.cell.2016.07.004