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

机译：脂质纳米盘中M2毒蕈碱受体-β-抑制蛋白复合物的结构

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摘要

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit beta-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis(1). Additionally, beta-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins(2). In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of beta-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of beta-arrestin 1 (beta arr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-beta arr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of beta arr1 to phosphorylated receptor residues and insertion of the finger loop of beta arr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G(o) protein complex(3). Moreover, the cryo-electron microscopy map reveals that the C-edge of beta arr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, beta arr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.
机译：通过激动剂激活后，G蛋白偶联受体（GPCR）募集β-arrestin，它使异三聚体G蛋白信号脱敏并促进受体胞吞作用（1）。此外，β-arrestin直接调节许多细胞信号通路，这些信号通路可诱导不同于G蛋白的细胞应答（2）。与G蛋白相比，G蛋白具有许多与GPCR复杂的高分辨率结构，与此相反，β-arrestin与GPCR相互作用的分子机制却鲜为人知。在这里，我们介绍了与脂质纳米盘中重构的M2毒蕈碱受体（M2R）结合的β-arrestin1（βarr1）的低温电子显微镜结构。 M2R-βarr1复合物显示出灵活相互作用的多峰网络，包括βarr1的N结构域与磷酸化受体残基的结合以及βarr1的指环插入M2R七跨膜束中，其构象与M2R-异三聚体G（o）蛋白复合物中的那个（3）。此外，冷冻电子显微镜图揭示了βarr1的C边缘参与脂质双层。通过原子模拟和生物物理，生化和细胞测定，我们表明C边缘对于稳定的复合物形成，βarr1募集，受体内在化和G蛋白活化的脱敏化至关重要。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功能性。

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  • 来源
    《Nature》 |2020年第7798期|297-302|共6页
  • 作者

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

  • 作者单位

    Duke Univ Med Ctr Dept Med Durham NC 27710 USA|Duke Univ Med Ctr Howard Hughes Med Inst Durham NC 27710 USA;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Chinese Univ Hong Kong Kobilka Inst Innovat Drug Discovery Sch Life & Hlth Sci Shenzhen Peoples R China;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Stanford Univ Sch Med Dept Struct Biol Stanford CA 94305 USA;

    Duke Univ Med Ctr Dept Med Durham NC 27710 USA|Duke Univ Med Ctr Howard Hughes Med Inst Durham NC 27710 USA|Univ Michigan Sch Med Ann Arbor MI USA;

    Duke Univ Med Ctr Dept Med Durham NC 27710 USA;

    Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA|Stanford Univ Dept Comp Sci Stanford CA 94305 USA|Stanford Univ Biophys Program Stanford CA 94305 USA;

    Duke Univ Med Ctr Dept Med Durham NC 27710 USA|Duke Univ Med Ctr Howard Hughes Med Inst Durham NC 27710 USA|Duke Univ Med Ctr Dept Biochem Durham NC 27710 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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