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<p>Membrane interactions play a crucial role in regulating arrestin activation and its binding to phosphorylated G protein-coupled receptors (GPCRs). Here, we combine in vitro biophysical approaches with cell-based fluorescence intensity fluctuation analysis to systematically compare the membrane-binding properties of the two highly conserved non-visual arrestin subtypes, arrestin-2 and arrestin-3. We find that in the absence of stimulation, arrestin-2 primarily engages PI(4,5)P<sub>2</sub>-enriched membranes through its C-edge and exhibits higher affinity than arrestin-3. When activated, arrestin-2, but not arrestin-3, predominantly shifts to using its finger loop to engage PI(4,5)P<sub>2</sub>-containing nanodiscs. Notably, while the lipid bilayer alone does not fully activate arrestin, it synergistically promotes arrestin-2/3 recruitment and enhances arrestin-2/3 activation in the presence of a phosphorylated GPCR C-tail. Live-cell tracking further reveals distinct plasma membrane interaction dynamics for arrestin-2 and arrestin-3 upon M<sub>2</sub> muscarinic acetylcholine receptor stimulation. Together, these findings uncover new mechanistic insights into arrestin activation and its functional interplay with membranes.</p>

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Distinct membrane binding properties of the two non-visual arrestins

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Thomas D. Killeen,
  • Katelyn Tepper,
  • Kyle W. Miller,
  • Yasmin Aydin,
  • Ya Zhuo,
  • Shuaitong Zhao,
  • Jason M. Conley,
  • Rachel Tat,
  • Candice S. Klug,
  • Adriano Marchese,
  • Valerică Raicu,
  • Qiuyan Chen

摘要

Membrane interactions play a crucial role in regulating arrestin activation and its binding to phosphorylated G protein-coupled receptors (GPCRs). Here, we combine in vitro biophysical approaches with cell-based fluorescence intensity fluctuation analysis to systematically compare the membrane-binding properties of the two highly conserved non-visual arrestin subtypes, arrestin-2 and arrestin-3. We find that in the absence of stimulation, arrestin-2 primarily engages PI(4,5)P2-enriched membranes through its C-edge and exhibits higher affinity than arrestin-3. When activated, arrestin-2, but not arrestin-3, predominantly shifts to using its finger loop to engage PI(4,5)P2-containing nanodiscs. Notably, while the lipid bilayer alone does not fully activate arrestin, it synergistically promotes arrestin-2/3 recruitment and enhances arrestin-2/3 activation in the presence of a phosphorylated GPCR C-tail. Live-cell tracking further reveals distinct plasma membrane interaction dynamics for arrestin-2 and arrestin-3 upon M2 muscarinic acetylcholine receptor stimulation. Together, these findings uncover new mechanistic insights into arrestin activation and its functional interplay with membranes.