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Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors.

Publication ,  Journal Article
Shukla, AK; Violin, JD; Whalen, EJ; Gesty-Palmer, D; Shenoy, SK; Lefkowitz, RJ
Published in: Proc Natl Acad Sci U S A
July 22, 2008

Beta-arrestins critically regulate G protein-coupled receptors (GPCRs), also known as seven-transmembrane receptors (7TMRs), both by inhibiting classical G protein signaling and by initiating distinct beta-arrestin-mediated signaling. The recent discovery of beta-arrestin-biased ligands and receptor mutants has allowed characterization of these independent "G protein-mediated" and "beta-arrestin-mediated" signaling mechanisms of 7TMRs. However, the molecular mechanisms underlying the dual functions of beta-arrestins remain unclear. Here, using an intramolecular BRET (bioluminescence resonance energy transfer)-based biosensor of beta-arrestin 2 and a combination of biased ligands and/or biased mutants of three different 7TMRs, we provide evidence that beta-arrestin can adopt multiple "active" conformations. Surprisingly, phosphorylation-deficient mutants of the receptors are also capable of directing similar conformational changes in beta-arrestin as is the wild-type receptor. This indicates that distinct receptor conformations induced and/or stabilized by different ligands can promote distinct and functionally specific conformations in beta-arrestin even in the absence of receptor phosphorylation. Our data thus highlight another interesting aspect of 7TMR signaling--i.e., functionally specific receptor conformations can be translated to downstream effectors such as beta-arrestins, thereby governing their functional specificity.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 22, 2008

Volume

105

Issue

29

Start / End Page

9988 / 9993

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Recombinant Fusion Proteins
  • Receptors, G-Protein-Coupled
  • Receptor, Angiotensin, Type 1
  • Protein Conformation
  • Phosphorylation
  • Mutagenesis, Site-Directed
  • Ligands
  • Humans
 

Citation

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Shukla, A. K., Violin, J. D., Whalen, E. J., Gesty-Palmer, D., Shenoy, S. K., & Lefkowitz, R. J. (2008). Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc Natl Acad Sci U S A, 105(29), 9988–9993. https://doi.org/10.1073/pnas.0804246105
Shukla, Arun K., Jonathan D. Violin, Erin J. Whalen, Diane Gesty-Palmer, Sudha K. Shenoy, and Robert J. Lefkowitz. “Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors.Proc Natl Acad Sci U S A 105, no. 29 (July 22, 2008): 9988–93. https://doi.org/10.1073/pnas.0804246105.
Shukla AK, Violin JD, Whalen EJ, Gesty-Palmer D, Shenoy SK, Lefkowitz RJ. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9988–93.
Shukla, Arun K., et al. “Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors.Proc Natl Acad Sci U S A, vol. 105, no. 29, July 2008, pp. 9988–93. Pubmed, doi:10.1073/pnas.0804246105.
Shukla AK, Violin JD, Whalen EJ, Gesty-Palmer D, Shenoy SK, Lefkowitz RJ. Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9988–9993.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

July 22, 2008

Volume

105

Issue

29

Start / End Page

9988 / 9993

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • Recombinant Fusion Proteins
  • Receptors, G-Protein-Coupled
  • Receptor, Angiotensin, Type 1
  • Protein Conformation
  • Phosphorylation
  • Mutagenesis, Site-Directed
  • Ligands
  • Humans