Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-UBA, Buenos Aires, Argentina.
Federated Department of Biological Sciences, New Jersey Institute of Technology & Rutgers University, Newark, NJ, United States.
NPJ Syst Biol Appl. 2021 Aug 17;7(1):32. doi: 10.1038/s41540-021-00192-8.
Covalent modification cycles (CMCs) are basic units of signaling systems and their properties are well understood. However, their behavior has been mostly characterized in situations where the substrate is in excess over the modifying enzymes. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations, leading to substrate sequestration by the enzymes. In this enzyme-in-excess regime, CMCs have been shown to exhibit signal termination, the ability of the product to return to a stationary value lower than its peak in response to constant stimulation, while this stimulation is still active, with possible implications for the ability of systems to adapt to environmental inputs. We characterize the conditions leading to signal termination in CMCs in the enzyme-in-excess regime. We also demonstrate that this behavior leads to a preferred frequency response (band-pass filters) when the cycle is subjected to periodic stimulation, whereas the literature reports that CMCs investigated so far behave as low-pass filters. We characterize the relationship between signal termination and the preferred frequency response to periodic inputs and we explore the dynamic mechanism underlying these phenomena. Finally, we describe how the behavior of CMCs is reflected in similar types of responses in the cascades of which they are part. Evidence of protein abundance in vivo shows that enzymes and substrates are present in comparable concentrations, thus suggesting that signal termination and frequency-preference response to periodic inputs are also important dynamic features of cell signaling systems, which have been overlooked.
共价修饰循环（CMCs）是信号系统的基本单位，其性质已得到很好的理解。然而，它们的行为主要是在底物超过修饰酶的情况下进行的。关于蛋白质丰度的实验数据表明，酶和其靶蛋白的浓度相当，导致酶对底物的隔离。在这种酶过量的情况下，已经表明 CMC 表现出信号终止，即产物能够在恒定刺激下返回低于其峰值的稳定值，而这种刺激仍然活跃，这可能对系统适应环境输入的能力产生影响。我们描述了导致 CMC 在酶过量情况下信号终止的条件。我们还证明，当循环受到周期性刺激时，这种行为会导致优先的频率响应（带通滤波器），而文献报道迄今为止研究的 CMC 表现为低通滤波器。我们描述了信号终止和对周期性输入的优先频率响应之间的关系，并探讨了这些现象背后的动态机制。最后，我们描述了 CMC 的行为如何反映在它们所组成的级联反应的类似类型的反应中。体内蛋白质丰度的证据表明，酶和底物的浓度相当，因此表明信号终止和对周期性输入的频率偏好反应也是细胞信号系统的重要动态特征，而这些特征一直被忽视。
