Kinetic diversity of amyloid oligomers
Kinetic diversity of amyloid oligomers
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淀粉样蛋白寡聚物的动力学多样性
DOI：
10.1073/pnas.1922267117
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发表时间：
2020-06-02
影响因子：
11.1
通讯作者：
Knowles, Tuomas P. J.
中科院分区：
文献类型：
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作者：
Dear, Alexander J.;Michaels, Thomas C. T.;Knowles, Tuomas P. J.
蛋白质自发组装成淀粉样纤维是许多越来越常见且目前无法治愈的人类疾病（包括阿尔茨海默病和帕金森病）的核心现象。寡聚物在此过程中短暂形成，不仅作为新细丝组装的必要中间体，而且也是这些疾病中的主要病原体。虽然淀粉样蛋白原纤维具有一个共同的，定义的一套物理化学特征，低聚物，相比之下，似乎更加多样化，它们的共性和差异迄今仍在很大程度上未被探索。在这里，我们使用化学动力学的框架来研究它们的动力学性质。通过拟合实验数据的几个不相关的淀粉样蛋白生成系统的新衍生的机械模型，我们发现，低聚物呈现出非常广泛的动力学和热力学稳定性，但它们具有两个属性是通用的：他们是压倒性的nonfibrillar，他们主要是解离回单体，而不是成熟成纤维状的物种。这些发现改变了我们对淀粉样蛋白低聚物和淀粉样蛋白原纤维之间关系的理解，并对其细胞毒性的性质具有重要意义。
The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochemical features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chemical kinetics to investigate their dynamical properties. By fitting experimental data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodynamic stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissociate back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.