Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation.
Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation.
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DOI：
10.1038/ncomms10948
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发表时间：
2016-03-24
影响因子：
16.6
通讯作者：
Knowles TP
中科院分区：
文献类型：
--
作者：
Arosio P;Michaels TC;Linse S;Månsson C;Emanuelsson C;Presto J;Johansson J;Vendruscolo M;Dobson CM;Knowles TP
越来越多的人认识到分子伴侣在调节淀粉样蛋白原纤维的形成中起关键作用，淀粉样蛋白原纤维的形成是与多种人类疾病相关的过程。然而，由于蛋白质聚集过程本身的高度复杂性，理解它们执行这一功能的详细机制一直具有挑战性。在这项工作中，我们建立在以前的动力学方法，并开发一个模型，认为成对分子伴侣和不同的蛋白质物种之间的相互作用，以确定蛋白质成分的伴侣和相应的微观反应步骤被抑制。我们表明，这些相互作用保留了未扰动反应网络的拓扑结构，但修改了不同微观步骤之间的连接性权重。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蛋白形成的微观机制的惊人多样性。 分子伴侣被认为是干扰蛋白质聚集，但其潜在的机制在很大程度上是未知的。在这里，作者开发了一个动力学模型，揭示了分子伴侣抑制淀粉样蛋白形成的各种不同的微观机制。
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. Molecular chaperones are recognized to interfere with protein aggregation, yet the underlying mechanisms are largely unknown. Here, the authors develop a kinetic model that reveals the variety of distinct microscopic mechanisms through which molecular chaperones act to suppress amyloid formation.