逮捕
G蛋白偶联受体
受体
磷酸化
细胞生物学
生物
跨膜结构域
蛋白质-蛋白质相互作用
信号转导
化学
生物化学
作者
Jagannath Maharana,Fumiya K Sano,Parishmita Sarma,Manish Kumar Yadav,Longhan Duan,Tomasz Maciej Stępniewski,Madhu Chaturvedi,Amit Ranjan,Vinay Kumar Singh,Sayantan Saha,G. R. Mahajan,Mohamed Chami,Wataru Shihoya,Jana Selent,Ka Young Chung,Rita Banerjee,Osamu Nureki,Arun K. Shukla
标识
DOI:10.1101/2023.07.05.547776
摘要
Abstract β-arrestins are multifunctional proteins that are critically involved in regulating spatio-temporal aspects of GPCR signaling. The interaction of β-arrestins with GPCRs is typically conceptualized in terms of receptor activation and phosphorylation primarily in the carboxyl-terminus. Interestingly however, there are several GPCRs that harbor majority of phosphorylation sites in their 3 rd intracellular loop (ICL3) instead of carboxyl-terminus but still robustly engage β-arrestins. Moreover, there are several 7TMRs that are now characterized as intrinsically-biased, β-arrestin-coupled receptors (ACRs) due to lack of functional G-protein-coupling but robust β-arrestin binding leading to functional outcomes. The molecular basis of β-arrestin interaction and activation upon binding to these types of 7TMRs is currently elusive, and it represents a major knowledge gap in our current understanding of this signaling system. Here, we present seven cryo-EM structures of β-arrestins in basal state, activated by the muscarinic M2 receptor (M2R) through its ICL3, and a β-arrestin-coupled receptor known as decoy D6 receptor (D6R). These structural snapshots combined with biochemical, cellular, and biophysical experiments including HDX-MS and MD simulation provide novel insights into the ability of β-arrestins to preferentially select specific phosphorylation patterns in the receptors, and also illuminate the structural diversity in 7TMR-β-arrestin interaction. Surprisingly, we also observe that the carboxyl-terminus of β-arrestin2 but not β-arrestin1 undergoes structural transition from a β-strand to α-helix upon activation by D6R, which may preclude the core-interaction with the activated receptor. Taken together, our study elucidates previously unappreciated aspects of 7TMR-β-arrestin interaction, and provides important mechanistic clues about how the two isoforms of β-arrestins can recognize and regulate a large repertoire of GPCRs.
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