Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, India.
PLoS One. 2021 Apr 30;16(4):e0250830. doi: 10.1371/journal.pone.0250830. eCollection 2021.
Activated phosphorylation-dephosphorylation biochemical reaction cycles are a class of enzymatic futile cycles. A futile cycle such as a single MAPK cascade governed by two underlying enzymatic reactions permits Hyperbolic (H), Signal transducing (ST), Threshold-hyperbolic (TH) and Ultrasensitive (U) operating regimes that characterize input-output behaviour. Retroactive signalling caused by load due to sequestration of phosphorylated or unphosphorylated form of the substrate in a single enzymatic cascade without explicit feedback can introduce two-way communication, a feature not possible otherwise. We systematically characterize the operating regimes of a futile cycle subject to retroactivity in either of the substrate forms. We demonstrate that increasing retroactivity strength, which quantifies the downstream load, can trigger five possible regime transitions. Retroactivity strength is a reflection of the fraction of the substrate sequestered by its downstream target. Remarkably, the minimum required retroactivity strength to evidence any sequestration triggered regime transition demands 23% of the substrate bound to its downstream target. This minimum retroactivity strength corresponds to the transition of the dose-response curve from ST to H regime. We show that modulation of the saturation and unsaturation levels of the enzymatic reactions by retroactivity is the fundamental mechanism governing operating regime transition.
激活的磷酸化-去磷酸化生化反应循环是一类酶促无效循环。 由两个基础酶反应控制的单个 MAPK 级联等无效循环允许双曲线 (H)、信号转导 (ST)、阈值双曲线 (TH) 和超灵敏 (U) 工作模式，这些模式特征是输入-输出行为。 由于底物的磷酸化或非磷酸化形式在单个酶级联中被隔离而导致的负载引起的回溯信号转导，而没有明确的反馈，可以引入双向通信，这是其他方式不可能实现的。 我们系统地描述了在任一种底物形式下受回溯影响的无效循环的工作模式。 我们证明，增加回溯强度（量化下游负载）可以引发五种可能的模式转变。 回溯强度反映了下游靶标隔离的底物分数。 值得注意的是，证据表明任何隔离触发的模式转变所需的最小回溯强度要求其下游靶标结合的底物的 23%。 这个最小回溯强度对应于剂量反应曲线从 ST 到 H 模式的转变。 我们表明，回溯通过对酶反应的饱和度和不饱和度的调节是控制工作模式转变的基本机制。
