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Updated: Dec 13, 2025

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Key phosphorylation sites in GPCRs orchestrate the contribution of β-Arrestin 1 in ERK1/2 activation

Mithu Baidya1, Punita Kumari1, Hemlata Dwivedi-Agnihotri1

  • 1Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.

EMBO Reports
|July 28, 2020
PubMed

Insights

Beta-arrestins (βarrs) regulate G protein-coupled receptor (GPCR) signaling. Engineering specific phosphorylation sites on GPCRs can alter βarr1

Area of Science:

  • Cellular signaling pathways
  • Molecular pharmacology
  • Biochemistry

Background:

  • Beta-arrestins (βarrs) are critical regulators of G protein-coupled receptor (GPCR) signaling and receptor trafficking.
  • Typically, βarr knockdown reduces agonist-induced ERK1/2 MAP kinase activation, but paradoxically enhances it for certain GPCRs.
  • The mechanistic basis for this opposing role of βarr1 in ERK1/2 activation remains elusive.

Purpose of the Study:

  • To investigate the correlation between the spatial arrangement of GPCR phosphorylation sites and the role of βarr1 in ERK1/2 activation.
  • To elucidate the molecular mechanisms underlying the dual role of βarr1 in GPCR-mediated signaling.

Main Methods:

  • Engineering of a double-phosphorylation-site cluster in the bradykinin receptor (B2R) to mimic the vasopressin receptor (V2R).
  • Utilizing an intrabody sensor to probe conformational changes.
  • Employing molecular dynamics simulations to analyze protein-protein interactions.

Main Results:

  • Engineering a double-phosphorylation-site cluster in B2R reversed βarr1's contribution to ERK1/2 activation from inhibitory to promotive.
  • An intrabody sensor indicated a conformational mechanism for βarr1's role reversal.
  • Molecular dynamics simulations revealed a bifurcated salt bridge interaction between the phosphorylated receptor and βarr1's lariat loop.

Conclusions:

  • GPCR phosphorylation site positioning dictates βarr1's function in ERK1/2 activation.
  • This finding offers insights into biased agonism and the development of novel therapeutics targeting GPCRs.
  • The study reveals a conformational mechanism for βarr1's context-dependent roles in signaling.
Keywords:
ERK1/2 MAP kinaseG protein-coupled receptorsbiased agonismcellular signalingβ-arrestins

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