Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA.
Department of Biochemistry and Biophysics, University of Rochester, Rochester, New York, USA.
Proteins. 2023 Jan;91(1):99-107. doi: 10.1002/prot.26413. Epub 2022 Aug 27.
Arrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell-signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modeling (ANM) together with our covariance compliment techniques to survey all the available structures of the nonvisual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain β-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.
arrestins 是在所有脊椎动物中表达的重要支架蛋白。它们在与活性 G 蛋白偶联受体 (GPCR) 结合后调节细胞信号事件，并触发活性 GPCR 的内吞作用。虽然 arrestins 的许多功能位点已经得到了描述，但这些位点如何相互作用的问题仍未得到解答。我们使用各向异性网络建模 (ANM) 结合协方差互补技术，对所有可用的非视觉 arrestins 结构进行了调查，以绘制结构变化和蛋白质结合如何影响它们的结构动力学。我们发现，激活和网格蛋白结合对 arrestin 动力学有显著影响，并且这些动力学变化局限于少数几个遥远的功能位点。这些位点包括 α 螺旋 1、套索环、核定位域和 C 环侧的 C 结构域 β 片层。我们的技术表明，网格蛋白结合和/或 GPCR 激活 arrestin 会干扰这些位点的动力学，而与结构变化无关。
