Kinetic network model to explain gain-of-function mutations in ERK2 enzyme
Kinetic network model to explain gain-of-function mutations in ERK2 enzyme
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DOI：
10.1063/1.5088647
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发表时间：
2019-04-21
影响因子：
4.4
通讯作者：
Kolomeisky, Anatoly B.
中科院分区：
文献类型：
--
作者：
Misiura, Mikita;Kolomeisky, Anatoly B.
ERK 2是属于Ras/Raf/MEK/ERK信号传导途径的激酶蛋白，其响应于一系列细胞外信号而被激活。这一级联系统的故障导致各种严重疾病，包括癌症。这通常是由属于级联的蛋白质突变引起的，即使在没有外部信号的情况下，也经常导致级联的异常高活性。1994年，在果蝇中发现了一种ERK 2蛋白质中的“功能获得性”突变，称为“七制造者”突变（D319 N）。该突变导致其他蛋白质与ERK 2的D位点的相互作用的破坏，并且与预期相反，导致其体内活性的增加。然而，到目前为止，还没有分子机制来解释这种效应。困难的是，这种突变应该同样负面影响ERK 2与所有底物，激活剂和失活剂的相互作用。在本文中，我们提出了一个半定量的动力学网络模型，给出了一个可能的解释增加活性的突变ERK 2物种。一个简化的生化网络ERK 2，被视为一个系统的耦合米氏过程，提出。其动力学特性的计算显式使用的方法首次通过过程。突变的影响与酶和底物之间的相互作用能强度的变化有关。结果发现，蛋白质的相互作用能的动力学性质的依赖是非单调的，这表明，一些突变可能会导致更有效的催化性能，尽管削弱分子间的相互作用。我们的理论预测同意与实验观察的七个制造商在ERK 2突变。也有人认为，突变的影响可能取决于底物的浓度。由AIP Publishing授权出版。
ERK2 is a kinase protein that belongs to a Ras/Raf/MEK/ERK signaling pathway, which is activated in response to a range of extracellular signals. Malfunctioning of this cascade leads to a variety of serious diseases, including cancers. This is often caused by mutations in proteins belonging to the cascade, frequently leading to abnormally high activity of the cascade even in the absence of an external signal. One such "gain-of-function" mutation in the ERK2 protein, called a "sevenmaker" mutation (D319N), was discovered in 1994 in Drosophila. The mutation leads to disruption of interactions of other proteins with the D-site of ERK2 and results, contrary to expectations, in an increase of its activity in vivo. However, no molecular mechanism to explain this effect has been presented so far. The difficulty is that this mutation should equally negatively affect interactions of ERK2 with all substrates, activators, and deactivators. In this paper, we present a semiquantitative kinetic network model that gives a possible explanation of the increased activity of mutant ERK2 species. A simplified biochemical network for ERK2, viewed as a system of coupled Michaelis-Menten processes, is presented. Its dynamic properties are calculated explicitly using the method of first passage processes. The effect of mutation is associated with changes in the strength of interaction energy between the enzyme and the substrates. It is found that the dependence of kinetic properties of the protein on the interaction energy is nonmonotonic, suggesting that some mutations might lead to more efficient catalytic properties, despite weakening intermolecular interactions. Our theoretical predictions agree with experimental observations for the sevenmaker mutation in ERK2. It is also argued that the effect of mutations might depend on the concentrations of substrates. Published under license by AIP Publishing.