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GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.

Publication ,  Journal Article
Asher, WB; Terry, DS; Gregorio, GGA; Kahsai, AW; Borgia, A; Xie, B; Modak, A; Zhu, Y; Jang, W; Govindaraju, A; Huang, L-Y; Inoue, A; Shi, L ...
Published in: Cell
May 12, 2022

β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in its basal state. Its engagement with a phosphopeptide mimicking phosphorylated receptor tail efficiently releases the β-arrestin tail from its N domain to assume distinct conformations. Unexpectedly, we find that β-arrestin binding to phosphorylated receptor, with a phosphorylation barcode identical to the isolated phosphopeptide, is highly inefficient and that agonist-promoted receptor activation is required for β-arrestin activation, consistent with the release of a sequestered receptor C tail. These findings, together with focused cellular investigations, reveal that agonism and receptor C-tail release are specific determinants of the rate and efficiency of β-arrestin activation by phosphorylated receptor. We infer that receptor phosphorylation patterns, in combination with receptor agonism, synergistically establish the strength and specificity with which diverse, downstream β-arrestin-mediated events are directed.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

May 12, 2022

Volume

185

Issue

10

Start / End Page

1661 / 1675.e16

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 1
  • Receptors, G-Protein-Coupled
  • Phosphorylation
  • Phosphopeptides
  • Developmental Biology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences
 

Citation

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Asher, W. B., Terry, D. S., Gregorio, G. G. A., Kahsai, A. W., Borgia, A., Xie, B., … Javitch, J. A. (2022). GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision. Cell, 185(10), 1661-1675.e16. https://doi.org/10.1016/j.cell.2022.03.042
Asher, Wesley B., Daniel S. Terry, G Glenn A. Gregorio, Alem W. Kahsai, Alessandro Borgia, Bing Xie, Arnab Modak, et al. “GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.Cell 185, no. 10 (May 12, 2022): 1661-1675.e16. https://doi.org/10.1016/j.cell.2022.03.042.
Asher WB, Terry DS, Gregorio GGA, Kahsai AW, Borgia A, Xie B, et al. GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision. Cell. 2022 May 12;185(10):1661-1675.e16.
Asher, Wesley B., et al. “GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision.Cell, vol. 185, no. 10, May 2022, pp. 1661-1675.e16. Pubmed, doi:10.1016/j.cell.2022.03.042.
Asher WB, Terry DS, Gregorio GGA, Kahsai AW, Borgia A, Xie B, Modak A, Zhu Y, Jang W, Govindaraju A, Huang L-Y, Inoue A, Lambert NA, Gurevich VV, Shi L, Lefkowitz RJ, Blanchard SC, Javitch JA. GPCR-mediated β-arrestin activation deconvoluted with single-molecule precision. Cell. 2022 May 12;185(10):1661-1675.e16.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

May 12, 2022

Volume

185

Issue

10

Start / End Page

1661 / 1675.e16

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 1
  • Receptors, G-Protein-Coupled
  • Phosphorylation
  • Phosphopeptides
  • Developmental Biology
  • 32 Biomedical and clinical sciences
  • 31 Biological sciences
  • 11 Medical and Health Sciences
  • 06 Biological Sciences