Molecular switch architecture determines response properties of signaling pathways
Molecular switch architecture determines response properties of signaling pathways
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DOI：
10.1073/pnas.2013401118
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发表时间：
2021-03-16
影响因子：
11.1
通讯作者：
Elston, Timothy C.
中科院分区：
文献类型：
--
作者：
Ghusinga, Khem Raj;Jones, Roger D.;Elston, Timothy C.
许多细胞内信号通路由分子开关、在两种状态之间转换的蛋白质组成。通常，当外部刺激激活其同源受体时，就会启动信号传导，从而导致下游开关使用以下机制之一从关闭状态转换为打开状态：激活，从关闭状态到打开状态的转换速率增加；去抑制，其中从开启状态到关闭状态的转变率降低；并且是协调一致的，其中激活和去抑制同时起作用。我们使用数学模型来比较这些信号机制的剂量反应曲线、响应时间和处理上游波动的能力。我们的分析阐明了分子开关的几个操作原理。首先，激活增加了该通路的敏感性，而去抑制则降低了敏感性。其次，激活产生的响应时间随着信号强度的增加而减少，而去抑制则导致响应时间随着信号强度的增加而增加。这些相反的特征使得协同机制不仅能够显示剂量反应的一致性，而且能够将响应时间与刺激强度分开。然而，这些潜在的有益特性是以增加对上游波动的敏感性为代价的。我们证明，当模型扩展到包含附加功能（例如受体去除、动力学校对和开关级联）时，这些操作原理也成立。总的来说，我们展示了分子开关的结构如何控制其响应特性。我们还讨论了我们的发现的生物学意义。
Many intracellular signaling pathways are composed of molecular switches, proteins that transition between two states-on and off. Typically, signaling is initiated when an external stimulus activates its cognate receptor that, in turn, causes downstream switches to transition from off to on using one of the following mechanisms: activation, in which the transition rate from the off state to the on state increases; derepression, in which the transition rate from the on state to the off state decreases; and concerted, in which activation and derepression operate simultaneously. We use mathematical modeling to compare these signaling mechanisms in terms of their dose-response curves, response times, and abilities to process upstream fluctuations. Our analysis elucidates several operating principles for molecular switches. First, activation increases the sensitivity of the pathway, whereas derepression decreases sensitivity. Second, activation generates response times that decrease with signal strength, whereas derepression causes response times to increase with signal strength. These opposing features allow the concerted mechanism to not only show dose-response alignment, but also to decouple the response time from stimulus strength. However, these potentially beneficial properties come at the expense of increased susceptibility to upstream fluctuations. We demonstrate that these operating principles also hold when the models are extended to include additional features, such as receptor removal, kinetic proofreading, and cascades of switches. In total, we show how the architecture of molecular switches govern their response properties. We also discuss the biological implications of our findings.