The catalytic nature of protein aggregation
The catalytic nature of protein aggregation
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DOI：
10.1063/1.5133635
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发表时间：
2020-01-31
影响因子：
4.4
通讯作者：
Knowles, Tuomas P. J.
中科院分区：
文献类型：
--
作者：
Dear, Alexander J.;Meisl, Georg;Knowles, Tuomas P. J.
由可溶性肽形成淀粉样原纤维是许多神经退行性疾病（例如阿尔茨海默病和帕金森病）的标志。对这些现象背后的微观反应过程的表征使人们对这些疾病的进展有了深入的了解，并可能为设计阻止这些疾病的药物的合理方法提供信息。实验证据表明，大多数这些反应过程本质上是催化性的，并且可能在生物系统的典型条件下表现出类酶饱和效应，但仍然缺乏解释这些饱和效应的统一建模框架。因此，在本文中，我们提出了生物丝形成的通用动力学模型，其中反应网络中的每个基本过程都可以催化。导出的单一闭合形式表达式能够高精度地描述生物丝形成的多种机制，并提供多个反应过程饱和的系统的第一个综合速率定律。此外，其前所未有的数学简单性使我们能够非常清楚地解释增加饱和度对整体动力学的影响。该模型的有效性通过将其与体外 A beta 40 聚集的数据进行拟合来说明。值得注意的是，我们发现初级成核变得饱和，这表明它必须是异质的，发生在界面而不是溶液中。
The formation of amyloid fibrils from soluble peptide is a hallmark of many neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Characterization of the microscopic reaction processes that underlie these phenomena have yielded insights into the progression of such diseases and may inform rational approaches for the design of drugs to halt them. Experimental evidence suggests that most of these reaction processes are intrinsically catalytic in nature and may display enzymelike saturation effects under conditions typical of biological systems, yet a unified modeling framework accounting for these saturation effects is still lacking. In this paper, we therefore present a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic. The single closed-form expression derived is capable of describing with high accuracy a wide range of mechanisms of biofilament formation and providing the first integrated rate law of a system in which multiple reaction processes are saturated. Moreover, its unprecedented mathematical simplicity permits us to very clearly interpret the effects of increasing saturation on the overall kinetics. The effectiveness of the model is illustrated by fitting it to the data of in vitro A beta 40 aggregation. Remarkably, we find that primary nucleation becomes saturated, demonstrating that it must be heterogeneous, occurring at interfaces and not in solution.