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.
Show 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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