Roles of protein ubiquitination and degradation kinetics in biological oscillations.
Roles of protein ubiquitination and degradation kinetics in biological oscillations.
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DOI：
10.1371/journal.pone.0034616
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Qu Z
中科院分区：
文献类型：
--
作者：
Xu L;Qu Z
蛋白质泛素化和降解在许多生物学功能中起重要作用，并与许多人类疾病有关。众所周知，要发生生化振荡，需要参与蛋白质的适当降解速率。在大多数生化反应的数学模型中，线性降解动力学已经被使用。然而，真实的系统中的降解动力学可能是非线性的，并且非线性降解动力学如何影响生物振荡还没有很好地理解。在本研究中，我们首先建立了一个蛋白质泛素化和降解的生化反应模型，并计算了降解速率与游离底物浓度的关系。我们发现，蛋白质降解动力学主要遵循Michaelis-Menten公式，具有由泛素化和去泛素化引起的时间延迟。然后，我们研究分析如何米氏降解动力学影响的不稳定性，导致振荡使用三个通用的振荡模型：1）正反馈介导的振荡器; 2）正加负反馈介导的振荡器;和3）负反馈介导的振荡器。在所有三种情况下，非线性降解动力学促进振荡，特别是对于负反馈介导的振荡器，导致比线性动力学观察到的振荡幅度大得多的振荡幅度和更慢的频率。然而，由于蛋白质泛素化和去泛素化的时间延迟通常抑制振荡，降低振幅并增加振荡的频率。这些理论分析提供了泛素化蛋白酶体系统中的特定蛋白质对生物振荡的影响机制的见解。
Protein ubiquitination and degradation play important roles in many biological functions and are associated with many human diseases. It is well known that for biochemical oscillations to occur, proper degradation rates of the participating proteins are needed. In most mathematical models of biochemical reactions, linear degradation kinetics has been used. However, the degradation kinetics in real systems may be nonlinear, and how nonlinear degradation kinetics affects biological oscillations are not well understood. In this study, we first develop a biochemical reaction model of protein ubiquitination and degradation and calculate the degradation rate against the concentration of the free substrate. We show that the protein degradation kinetics mainly follows the Michaelis-Menten formulation with a time delay caused by ubiquitination and deubiquitination. We then study analytically how the Michaelis-Menten degradation kinetics affects the instabilities that lead to oscillations using three generic oscillation models: 1) a positive feedback mediated oscillator; 2) a positive-plus-negative feedback mediated oscillator; and 3) a negative feedback mediated oscillator. In all three cases, nonlinear degradation kinetics promotes oscillations, especially for the negative feedback mediated oscillator, resulting in much larger oscillation amplitudes and slower frequencies than those observed with linear kinetics. However, the time delay due to protein ubiquitination and deubiquitination generally suppresses oscillations, reducing the amplitude and increasing the frequency of the oscillations. These theoretical analyses provide mechanistic insights into the effects of specific proteins in the ubiquitination-proteasome system on biological oscillations.
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