Molecular switch architecture determines response properties of signaling pathways

Abstract

Many intracellular signaling pathways are composed of molecular switches, proteins that transition between two states-<i>on</i> and <i>off</i> Typically, signaling is initiated when an external stimulus activates its cognate receptor that, in turn, causes downstream switches to transition from <i>off</i> to <i>on</i> using one of the following mechanisms: activation, in which the transition rate from the <i>off</i> state to the <i>on</i> state increases; derepression, in which the transition rate from the <i>on</i> state to the <i>off</i> 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.