小柯机器人

分子伴侣调节α-突触核蛋白
2019-12-06 11:16

瑞士巴塞尔大学Sebastian Hiller、Björn M. Burmann与苏黎世联邦理工学院Roland Riek等研究人员合作揭示了哺乳动物细胞中分子伴侣对α-突触核蛋白的调节。2019年12月4日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员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。研究人员发现,六个极为不同的分子伴侣通常识别α-突触核蛋白中的一个典型基序,由N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-突触核蛋白显著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。这项研究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,并为帕金森氏病的治疗性干预提供了新的视角。

据介绍,帕金森氏病患者的神经退行性变与路易体的发生有关,这是细胞内的包裹体,其中包含内在无序的蛋白质α-突触核蛋白的聚集体。α-突触核蛋白在细胞中的聚集倾向受到特定因素的调节,这些因素包括翻译后修饰、Abelson激酶介导的磷酸化以及与细胞内机制如分子伴侣的相互作用,尽管其潜在机制尚不清楚。

附:英文原文

Title: Regulation of α-synuclein by chaperones in mammalian cells

Author: Bjrn M. Burmann, Juan A. Gerez, Irena Mateko-Burmann, Silvia Campioni, Pratibha Kumari, Dhiman Ghosh, Adam Mazur, Emelie E. Aspholm, Darius ulskis, Magdalena Wawrzyniuk, Thomas Bock, Alexander Schmidt, Stefan G. D. Rdiger, Roland Riek, Sebastian Hiller

Issue&Volume: 2019-12-04

Abstract: Neurodegeneration in patients with Parkinsons disease is correlated with the occurrence of Lewy bodiesintracellular inclusions that contain aggregates of the intrinsically disordered protein -synuclein1. The aggregation propensity of -synuclein in cells is modulated by specific factors that include post-translational modifications2,3, Abelson-kinase-mediated phosphorylation4,5 and interactions with intracellular machineries such as molecular chaperones, although the underlying mechanisms are unclear68. Here we systematically characterize the interaction of molecular chaperones with -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 -synuclein, consisting of the N terminus and a segment around Tyr39, and hinder the aggregation of -synuclein. NMR experiments9 in cells show that the same transient interaction pattern is preserved inside living mammalian cells. Specific inhibition of the interactions between -synuclein and the chaperone HSC70 and members of the HSP90 family, including HSP90, results in transient membrane binding and triggers a remarkable re-localization of -synuclein to the mitochondria and concomitant formation of aggregates. Phosphorylation of -synuclein at Tyr39 directly impairs the interaction of -synuclein with chaperones, thus providing a functional explanation for the role of Abelson kinase in Parkinsons disease. Our results establish a master regulatory mechanism of -synuclein function and aggregation in mammalian cells, extending the functional repertoire of molecular chaperones and highlighting new perspectives for therapeutic interventions for Parkinsons disease. Chaperones interact with a canonical motif in -synuclein, which can be prevented by phosphorylation of -synuclein at Tyr39, whereas inhibition of this interaction leads to the localization of -synuclein to the mitochondria and aggregate formation.

DOI: 10.1038/s41586-019-1808-9

Source:https://www.nature.com/articles/s41586-019-1808-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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