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Related Experiment Videos

Activation-dependent conformational changes in {beta}-arrestin 2.

Kunhong Xiao1, Sudha K Shenoy, Kelly Nobles

  • 1Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

The Journal of Biological Chemistry
|October 27, 2004
PubMed
Summary
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Beta-arrestin 2 undergoes conformational changes upon binding to activated vasopressin receptors, releasing its C terminus and enhancing clathrin binding. This study reveals how receptor activation transforms beta-arrestin 2 into its active state.

Area of Science:

  • Molecular Cell Biology
  • Biochemistry
  • Structural Biology

Background:

  • Beta-arrestins (arrestin 2) are key adaptor proteins mediating seven membrane-spanning receptor (7MSR) signaling, desensitization, and endocytosis.
  • While inactive structures exist, the conformational changes in beta-arrestins upon activated receptor binding remain poorly understood.
  • Understanding these dynamics is crucial for deciphering 7MSR signaling pathways.

Purpose of the Study:

  • To characterize the conformational changes in beta-arrestin 2 upon binding to an activated, phosphorylated vasopressin type II receptor (V(2)R) phosphopeptide.
  • To investigate the functional consequences of these conformational changes, particularly regarding clathrin binding.
  • To establish an in vitro system for modeling receptor-beta-arrestin interactions.

Main Methods:

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  • Limited tryptic proteolysis and MALDI-TOF mass spectrometry were used to compare beta-arrestin 2 in the presence of a V(2)R phosphopeptide (V(2)R-pp) versus a nonphosphopeptide (V(2)R-np).
  • The effects of heparin binding on beta-arrestin 2 conformation were also assessed.
  • Clathrin binding assays were performed to quantify changes in affinity.

Main Results:

  • V(2)R-pp specifically binds beta-arrestin 2, inducing conformational changes including C-terminal release (revealing Arg(394)) and N-terminal rearrangement (shielding Arg(8)).
  • Heparin binding also releases the C terminus but differs from V(2)R-pp induced changes, suggesting distinct binding sites or mechanisms.
  • C-terminal release significantly enhances beta-arrestin 2's clathrin binding affinity by 10-fold, by increasing accessibility of the clathrin binding site.

Conclusions:

  • The V(2)R-pp peptide effectively activates beta-arrestin 2 in vitro, mimicking activated phosphorylated 7MSRs.
  • This study provides the first direct evidence of beta-arrestin 2 conformational changes during its transition from an inactive to an active state.
  • The findings establish a valuable in vitro model for studying receptor-arrestin interactions and their functional outcomes.