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Catalytic activation of β-arrestin by GPCRs

机译：GPCR催化活化β-arrestin

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摘要

beta-arrestins are critical regulator and transducer proteins for G-protein-coupled receptors (GPCRs). beta-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-beta-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of beta-arrestin activation that does not require stable GPCR-beta-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in beta-arrestin. This promotes capture of beta-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. beta-arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a beta-arrestin-dependent component of the cellular ERK (extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular beta-arrestin function that is activated catalytically by GPCRs.
机译：β-arrestins是G蛋白偶联受体（GPCR）的关键调节剂和传感器蛋白。人们普遍认为，β-arrestin可通过形成稳定且化学计量的GPCR-β-arrestin支架复合物而被激活，这需要并由GPCR的磷酸化尾部驱动。在这里，我们证明了β-arrestin激活的独特和附加机制，不需要稳定的GPCR-β-arrestin支架或GPCR尾部。相反，它是通过GPCR核心的瞬时参与而发生的，这会破坏β-arrestin中保守的域间电荷网络的稳定性。从GPCR解离后，这会促进β-arrestin在质膜上的捕获，并促进其在网格蛋白包被的内吞结构（CCS）中的积累，从而需要与膜磷酸肌醇和CCS-晶格蛋白进行一系列相互作用。在没有上游激活GPCR的情况下，CCS中的β-arrestin聚集与细胞ERK（细胞外信号调节激酶）反应的β-arrestin依赖性成分有关。这些结果描绘了由GPCR催化激活的细胞β-arrestin功能的离散机制。

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  • 来源
    《Nature》 |2018年第7705期|381-386|共6页
  • 作者

    Eichel Kelsie; Jullie Damien; Barsi-Rhyne Benjamin; Latorraca Naomi R.; Masureel Matthieu; Sibarita Jean-Baptiste; Dror Ron O.; von Zastrow Mark;

  • 作者单位

    Univ Calif San Francisco, Sch Med, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Sch Med, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA;

    Univ Calif San Francisco, Sch Med, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA;

    Stanford Univ, Biophys Program, Stanford, CA 94305 USA;

    Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA;

    Ctr Natl Rech Sci, Interdisciplinary Inst Neurosci, UMR 5297, Bordeaux, France;

    Stanford Univ, Biophys Program, Stanford, CA 94305 USA;

    Univ Calif San Francisco, Sch Med, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 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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