Distinct membrane binding properties of the two non-visual arrestins. Commun Biol 2026 Jan 07;9(1):150
Date
01/08/2026Pubmed ID
41501442Pubmed Central ID
PMC12868637DOI
10.1038/s42003-025-09428-3Scopus ID
2-s2.0-105029263916 (requires institutional sign-in at Scopus site)Abstract
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.
Author List
Killeen TD, Tepper K, Miller KW, Aydin Y, Zhuo Y, Zhao S, Conley JM, Tat R, Klug CS, Marchese A, Raicu V, Chen QAuthor
Candice S. Klug PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsArrestins
Cell Membrane
HEK293 Cells
Humans
Protein Binding
