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Regulation of α-synuclein by chaperones in mammalian cells

机译：伴侣蛋白在哺乳动物细胞中对α-突触核蛋白的调控

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摘要

Neurodegeneration in patients with Parkinson's disease is correlated with the occurrence of Lewy bodies-intracellular inclusions that contain aggregates of the intrinsically disordered protein alpha-synuclein(1). The aggregation propensity of alpha-synuclein in cells is modulated by specific factors that include post-translational modifications(2,3), Abelson-kinase-mediated phosphorylation(4,5) and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear(6-8). Here we systematically characterize the interaction of molecular chaperones with alpha-synuclein in vitro as well as in cells at the atomic level. We find that six highly divergent molecular chaperones commonly recognize a canonical motif in alpha-synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of alpha-synuclein. NMR experiments(9) in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between alpha-synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90 beta, results in transient membrane binding and triggers a remarkable re-localization of alpha-synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of alpha-synuclein at Tyr39 directly impairs the interaction of alpha-synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinson's disease. Our results establish a master regulatory mechanism of alpha-synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinson's disease.
机译：帕金森氏病患者的神经变性与路易小体的发生有关-路易小体-细胞内包裹物包含本质上无序的蛋白质α-突触核蛋白的聚集体（1）。 α-突触核蛋白在细胞中的聚集倾向受特定因素的调节，这些因素包括翻译后修饰（2,3），Abelson激酶介导的磷酸化（4,5）以及与细胞内机制（例如分子伴侣）的相互作用。机制尚不清楚（6-8）。在这里，我们系统地表征了分子伴侣与α-突触核蛋白在体外以及在原子级细胞中的相互作用。我们发现六个高度不同的分子伴侣通常识别α-突触核蛋白中的一个正则基序，由N末端和Tyr39周围的一个片段组成，并阻碍了α-突触核蛋白的聚集。细胞中的NMR实验（9）表明，在活的哺乳动物细胞内保留了相同的瞬时相互作用模式。对α-突触核蛋白与分子伴侣HSC70和HSP90家族成员（包括HSP90β）之间的相互作用的特异性抑制，导致瞬时膜结合，并触发α-突触核蛋白显着地重新定位于线粒体，并随之形成聚集体。 Tyr39处α-突触核蛋白的磷酸化直接削弱了α-突触核蛋白与分子伴侣的相互作用，从而为Abelson激酶在帕金森氏病中的作用提供了功能解释。我们的结果建立了哺乳动物细胞中α-突触核蛋白功能和聚集的主要调控机制，扩展了分子伴侣的功能范围，并突出了帕金森氏病治疗干预的新观点。

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  • 来源
    《Nature》 |2020年第7788期|127-132|共6页
  • 作者

    Burmann Bjorn M.; Gerez Juan A.; Matecko-Burmann Irena; Campioni Silvia; Kumari Pratibha; Ghosh Dhiman; Mazur Adam; Aspholm Emelie E.; Sulskis Darius; Wawrzyniuk Magdalena; Bock Thomas; Schmidt Alexander; Rudiger Stefan G. D.; Riek Roland; Hiller Sebastian;

  • 作者单位

    Univ Basel Biozentrum Basel Switzerland|Univ Gothenburg Dept Chem & Mol Biol Gothenburg Sweden|Univ Gothenburg Wallenberg Ctr Mol & Translat Med Gothenburg Sweden;

    ETH Dept Chem & Appl Biosci Lab Phys Chem Zurich Switzerland;

    Univ Basel Biozentrum Basel Switzerland|Univ Gothenburg Wallenberg Ctr Mol & Translat Med Gothenburg Sweden|Univ Gothenburg Dept Psychiat & Neurochem Gothenburg Sweden;

    ETH Dept Chem & Appl Biosci Lab Phys Chem Zurich Switzerland|Empa Dept Funct Mat Cellulose & Wood Mat Lab Dubendorf Switzerland;

    Univ Basel Biozentrum Basel Switzerland;

    Univ Gothenburg Dept Chem & Mol Biol Gothenburg Sweden|Univ Gothenburg Wallenberg Ctr Mol & Translat Med Gothenburg Sweden;

    Univ Utrecht Cellular Prot Chem Bijvoet Ctr Biomol Res & Sci Life Utrecht Netherlands|Univ Utrecht Dept Infect Dis & Immunol Utrecht Netherlands;

    Univ Utrecht Cellular Prot Chem Bijvoet Ctr Biomol Res & Sci Life Utrecht Netherlands;

  • 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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