2022年11月10日，《细胞》杂志在线发表了美国科学家的一项最新研究成果。来自斯坦福大学医学院的Brian K. Kobilka等研究人员合作发现，膜磷酸肌醇调节GPCR-β-阻遏蛋白复合体的组装和动态变化。

研究人员表示，阻遏蛋白与磷酸化的G蛋白偶联受体（GPCR）的结合对于调节信号传导至关重要。一旦内吞，一些GPCR保持与β-阻遏蛋白的结合，而其他GPCR仅有短暂的互动；这种差异影响了GPCR的信号传导和循环。基于细胞和体外生物物理实验揭示了膜磷酸肌醇（PIP）在β-阻遏蛋白招募和GPCR-β-阻遏蛋白复合物动态中的作用。

研究人员发现，GPCR大致分为两组，一组需要PIP结合才能招募β-阻遏蛋白，另一组则不需要。质膜PIP增强了β-阻遏蛋白的活性构象，并通过促进复合物的完全参与状态来稳定GPCR-β-阻遏蛋白复合物。作为GPCR-β-阻遏蛋白复合体动力学的异构调节剂，膜PIP允许额外的构象多样性，而不是仅仅由GPCR磷酸化施加。对于需要膜PIP结合来招募β-阻遏蛋白的GPCR来说，这提供了一个在GPCR转位到内体时释放β-阻遏蛋白的机制，从而使其能够快速回收。

附：英文原文

Title: Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics

Author: John Janetzko, Ryoji Kise, Benjamin Barsi-Rhyne, Dirk H. Siepe, Franziska M. Heydenreich, Kouki Kawakami, Matthieu Masureel, Shoji Maeda, K. Christopher Garcia, Mark von Zastrow, Asuka Inoue, Brian K. Kobilka

Issue&Volume: 2022-11-10

Abstract: Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for β-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for β-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.

DOI: 10.1016/j.cell.2022.10.018

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01360-5