动力学分析揭示了分子伴侣抑制淀粉样蛋白形成的微观机制的多样性。

Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation.

作者信息

Arosio Paolo, Michaels Thomas C T, Linse Sara, Månsson Cecilia, Emanuelsson Cecilia, Presto Jenny, Johansson Jan, Vendruscolo Michele, Dobson Christopher M, Knowles Tuomas P J

机构信息

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.

Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.

出版信息

Nat Commun. 2016 Mar 24;7:10948. doi: 10.1038/ncomms10948.

Abstract

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation.

摘要

人们越来越认识到分子伴侣在调节淀粉样纤维形成过程中起着关键作用,这一过程与多种人类疾病相关。然而,由于蛋白质聚集过程本身极为复杂,了解它们执行此功能的详细机制一直具有挑战性。在这项工作中,我们基于先前的动力学方法,开发了一个模型,该模型考虑分子伴侣与不同蛋白质种类之间的成对相互作用,以识别分子伴侣靶向的蛋白质成分以及被抑制的相应微观反应步骤。我们表明,这些相互作用保留了未受干扰的反应网络的拓扑结构,但改变了不同微观步骤之间的连接权重。此外,通过分析几种蛋白质 - 分子伴侣系统,我们揭示了分子伴侣抑制淀粉样形成的微观机制中的显著多样性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2329/4820785/4c25b07d73b8/ncomms10948-f1.jpg

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