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bioRxiv · 10.1101/2025.04.05.647240

β-Arrestin Condensates Regulate G Protein-Coupled Receptor Function

Anderson, P.·Xiao, P.·Zhong, Y.·Kaakati, A.·Alfonso-DeSouza, J.·Zhang, T.·Zhang, C.·Qi, L.·Ding, W.·Liu, S.·Pani, B.·Krishnan, A.·Chen, O.·Jassal, C.·Strawn, J.·Sun, J.·Rajagopal, S.
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Abstract

G protein-coupled receptors (GPCRs) are the largest class of receptors in the genome and control many signaling cascades essential for survival. GPCR signaling is regulated by {beta}-arrestins, multifunctional adapter proteins that direct receptor desensitization, internalization, and signaling. While at many GPCRs, {beta}-arrestins interact with a wide array of signaling effectors, it is unclear how {beta}-arrestins promote such varied functions. Here we show that {beta}-arrestins undergo liquid-liquid phase separation (LLPS) to form condensates that regulate GPCR function. We demonstrate that {beta}-arrestin oligomerization occurs in proximity to the GPCR and regulates GPCR functions such as internalization and signaling. This model is supported by a cryoEM structure of the adhesion receptor ADGRE1 in a 2:2 complex with {beta}-arrestin 1, with a {beta}-arrestin orientation that can promote oligomerization. Our work provides a paradigm for {beta}-arrestin condensates as regulators of GPCR function, with LLPS serving as an important promoter of signaling compartmentalization at GPCRs.

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Anderson, P., Xiao, P., Zhong, Y., Kaakati, A., Alfonso-DeSouza, J., Zhang, T., Zhang, C., Qi, L., Ding, W., Liu, S., Pani, B., Krishnan, A., Chen, O., Jassal, C., Strawn, J., Sun, J., Rajagopal, S.. 2025-04-05. β-Arrestin Condensates Regulate G Protein-Coupled Receptor Function. https://doi.org/10.1101/2025.04.05.647240

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