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July 1st, 2025
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Harvard Medical School
biochemistry
biorxiv

β-arrestin recruitment facilitates a direct association with G proteins

Lee, C. Y.Open in Google Scholar•Smith, J. S.Open in Google Scholar•Kohlmann, T.Open in Google Scholar•Meara, E. M.Open in Google Scholar•Pham, U.Open in Google Scholar•Kwarcinski, F.Open in Google Scholar•Dates, A. N.Open in Google Scholar•Choi, I.Open in Google Scholar•Hilibrand, A. S.Open in Google Scholar•Gillikin, A.Open in Google Scholaret al.

G protein-coupled receptors (GPCRs) are targets for almost a third of all FDA-approved drugs. GPCRs are known to signal through both heterotrimeric G proteins and {beta}-arrestins. Traditionally these pathways were viewed as largely separable, with G proteins primarily initiating downstream signaling while {beta}-arrestins modulate receptor trafficking and desensitization in addition to regulating their own signaling events. Recent studies suggest an integrated role of G proteins and {beta}-arrestins in GPCR signaling, however the cellular and biochemical requirements for G protein: {beta}-arrestin interactions remain unclear. Here we show that G proteins and {beta}-arrestins can directly interact. Through utilization of {beta}-arrestin-biased receptors and artificially enforced {beta}-arrestin relocalization, we demonstrate that recruitment of {beta}-arrestin to the plasma membrane is sufficient to interact with the G protein Gi. Using purified proteins, we show that Gi directly interacts with {beta}-arrestin. In addition, we find that Gi family members differ in their degree of association with {beta}-arrestin, and that a large degree of this selectivity resides within the alpha helical domain of Gi. These findings delineate the cellular and biochemical conditions that drive direct interactions between G proteins and {beta}-arrestins and illuminate the molecular basis for how they work together to effect GPCR signaling.

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