Sensitivity and Frequency Response of Biochemical Cascades.
Sensitivity and Frequency Response of Biochemical Cascades.
复制标题
生化级联的灵敏度和频率响应。
DOI：
10.1101/2023.09.14.557821
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Sauro,HerbertM
中科院分区：
文献类型：
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作者：
Kochen,MichaelA;Hellerstein,JosephL;Sauro,HerbertM
从细胞表面到细胞质和核靶的信号转导是通过相互连接的复杂网络进行的。磷酸化循环是许多途径的共同组成部分，可以采取多层循环级联的形式，或者将具有多个磷酸化位点的物种结合在一起，从而有效地创建一系列具有不断增加的磷酸化状态的循环。这项工作的重点是这类系统的频率响应和灵敏度，这两个性质还没有得到彻底的研究。从一个单一的磷酸化的单周期系统开始，我们比较了稳态下不同输入信号强度范围内对微扰的敏感性。接着进行了频率响应分析，重点分析了增益和相关带宽。接下来，我们考虑一个两层级联的单一磷酸化循环，并集中在两个循环如何相互作用，以产生不同的影响带宽和阻尼性。然后我们考虑双磷酸化体系的(超)灵敏度，其中我们详细描述了一阶超灵敏度，这是这些系统的一个独特的性质，它可以与零阶超灵敏度混合来创建在一系列信号输入范围内具有相对恒定增益的系统。最后，我们对n-磷酸化体系的灵敏度进行了深入的分析。
Signal transduction from a cell’s surface to cytoplasmic and nuclear targets takes place through a complex network of interconnected pathways. Phosphorylation cycles are common components of many pathways and may take the form of a multi-layered cascade of cycles or incorporate species with multiple phosphorylation sites that effectively create a sequence of cycles with increasing states of phosphorylation. This work focuses on the frequency response and sensitivity of such systems, two properties that have not been thoroughly examined. Starting with a singularly phosphorylated single-cycle system, we compare the sensitivity to perturbation at steady-state across a range of input signal strengths. This is followed by a frequency response analysis focusing on the gain and associated bandwidth. Next, we consider a two-layer cascade of single phosphorylation cycles and focus on how the two cycles interact to produce various effects on the bandwidth and damping properties. Then we consider the (ultra)sensitivity of a doubly phosphorylated system, where we describe in detail first-order ultrasensitivity, a unique property of these systems, which can be blended with zero-order ultrasensitivity to create systems with relatively constant gain over a range of signal input. Finally, we give an in-depth analysis of the sensitivity of an n-phosphorylated system.