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

Publication ,  Journal Article
Thomsen, ARB; Plouffe, B; Cahill, TJ; Shukla, AK; Tarrasch, JT; Dosey, AM; Kahsai, AW; Strachan, RT; Pani, B; Mahoney, JP; Huang, L; Breton, B ...
Published in: Cell
August 11, 2016

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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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

August 11, 2016

Volume

166

Issue

4

Start / End Page

907 / 919

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Multiprotein Complexes
  • Microscopy, Electron
  • Microscopy, Confocal
  • Humans
  • HEK293 Cells
  • GTP-Binding Protein alpha Subunits, Gs
  • Endosomes
 

Citation

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Thomsen, A. R. B., Plouffe, B., Cahill, T. J., Shukla, A. K., Tarrasch, J. T., Dosey, A. 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
Thomsen, Alex R. B., Bianca Plouffe, Thomas J. Cahill, Arun K. Shukla, Jeffrey T. Tarrasch, Annie M. Dosey, Alem W. Kahsai, et al. “GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.Cell 166, no. 4 (August 11, 2016): 907–19. https://doi.org/10.1016/j.cell.2016.07.004.
Thomsen ARB, Plouffe B, Cahill TJ, Shukla AK, Tarrasch JT, Dosey AM, et al. GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling. Cell. 2016 Aug 11;166(4):907–19.
Thomsen, Alex R. B., et al. “GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling.Cell, vol. 166, no. 4, Aug. 2016, pp. 907–19. Pubmed, doi:10.1016/j.cell.2016.07.004.
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. GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling. Cell. 2016 Aug 11;166(4):907–919.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

August 11, 2016

Volume

166

Issue

4

Start / End Page

907 / 919

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Signal Transduction
  • Receptors, G-Protein-Coupled
  • Multiprotein Complexes
  • Microscopy, Electron
  • Microscopy, Confocal
  • Humans
  • HEK293 Cells
  • GTP-Binding Protein alpha Subunits, Gs
  • Endosomes