Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 950 Atlantic Drive, Atlanta, GA 30332, USA.
Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd, Atlanta, GA 30322, USA.
Biomolecules. 2021 Nov 22;11(11):1741. doi: 10.3390/biom11111741.
Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through the posttranslational modification (PTM) cycle of signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant, as by the classical Koshland-Goldbeter model. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here, we use mathematical models to explore the signal amplification properties in such scenarios and report some novel aspects. Our analyses indicate that PTM-induced protein stabilization brings the enzymes closer to saturation. As a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response, higher magnitude, and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Importantly, ultrasensitivity is not limited to modified or unmodified protein substrates-when protein turnover is considered, the total free protein substrate can also exhibit ultrasensitivity under several conditions. When full enzymatic reactions are used instead of Michaelis-Menten kinetics for the modeling, the total free protein substrate can even exhibit nonmonotonic dose-response patterns. It is conceivable that cells use inducible protein stabilization as a strategy in the signaling network to boost signal amplification while saving energy by keeping the protein substrate levels low at basal conditions.
生物分子网络中的信号放大将线性输入转换为陡峭的 S 形输出，是许多细胞功能的核心，包括增殖、分化、动态平衡、适应和生物节律。一种典型的信号放大基序是零级超敏性，它通过信号蛋白的翻译后修饰 (PTM) 循环来介导。这个信号基序的功能通常是通过假设蛋白质底物的总量保持不变来进行检查的，就像经典的 Koshland-Goldbeter 模型一样。然而，信号蛋白的共价修饰通常会导致其稳定性发生变化，从而影响蛋白质底物的丰度。在这里，我们使用数学模型来探索这种情况下的信号放大特性，并报告一些新的方面。我们的分析表明，PTM 诱导的蛋白质稳定性使酶更接近饱和。结果，超敏性可能会出现或大大增强，具有更陡峭的 S 形响应、更高的幅度和通常更长的响应时间。在 PTM 使蛋白质不稳定的情况下，通过改变参与酶的活性或增加蛋白质合成，可以恢复超敏性。重要的是，超敏性不仅限于修饰或未修饰的蛋白质底物——当考虑蛋白质周转时，在几种条件下，总游离蛋白质底物也可以表现出超敏性。当完全酶反应而不是米氏动力学用于建模时，总游离蛋白质底物甚至可以表现出非单调剂量反应模式。可以想象，细胞在信号网络中使用诱导的蛋白质稳定性作为一种策略来增强信号放大，同时在基础条件下通过保持蛋白质底物水平低来节省能量。
