美国斯坦福大学医学院Georgios Skiniotis与杜克大学Robert J. Lefkowitz等研究人员合作揭示了M2毒蕈碱受体与β-arrestin的复合物结构。2020年1月16日，《自然》在线发表了这项成果。

研究人员报道了重构在脂质纳米盘中的毒蕈碱型乙酰胆碱-2-受体（M2R）与β-arrestin1（βarr1）形成复合物的冷冻电镜（cryo-EM）结构。M2R–βarr1结构显示了柔性相互作用的多模态网络，包括βarr1N结构域与磷酸化受体残基的结合以及βarr1指环插入M2R七跨膜束中，其构象类似于M2R-异三聚体Go蛋白质结构。此外，cryoEM图揭示了βarr1C结构域边缘与脂质双层结合。通过原子模拟、生物物理、生化和细胞分析，研究人员表明C边缘对于稳定的复合物形成、βarr1募集、受体內吞以及对G蛋白活化的脱敏作用至关重要。综上所述，这些数据表明β-arrestin与受体和磷脂双层的协同相互作用有助于其功能的多样性。

据介绍，被激动剂激活后，G蛋白偶联受体（GPCR）募集β-arrestin，从而使异三聚体G蛋白信号转脱敏并促进受体胞吞作用。此外，β-arrestin直接调节许多细胞信号通路，从而诱导不同于G蛋白的细胞应答。

附：英文原文

Title: Structure of the M2 muscarinic receptor–β-arrestin complex in a lipid nanodisc

Author: Dean P. Staus, Hongli Hu, Michael J. Robertson, Alissa L. W. Kleinhenz, Laura M. Wingler, William D. Capel, Naomi R. Latorraca, Robert J. Lefkowitz, Georgios Skiniotis

Issue&Volume: 2020-01-16

Abstract: Following agonist activation, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins2. Here we present a cryo-electron microscopy (cryo-EM) structure of β-arrestin 1 (βarr1) in complex with muscarinic acetylcholine-2-receptor (M2R) reconstituted in lipid nanodiscs. The M2R–βarr1 structure shows a multimodal network of flexible interactions, including binding of the βarr1 N domain to phosphorylated receptor residues and βarr1 finger loop insertion into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein structure3. Moreover, the cryoEM map reveals that the βarr1 C-domain edge engages the lipid bilayer. Through atomistic simulations, biophysical, biochemical, and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest the cooperative interactions of β-arrestin with both the receptor and phospholipid bilayer contribute to its functional versatility.

DOI: 10.1038/s41586-020-1954-0

Source: https://www.nature.com/articles/s41586-020-1954-0