A nested bistable module within a negative feedback loop ensures different types of oscillations in signaling systems

JUAN IGNACIO MARRONE; JACQUES-A. SEPULCHRE; ALEJANDRA C VENTURA

Buenos Aires

Simposio; I Simposio de Modelado Multiescala para Biociencias y Nanomateriales en Argentina; 2022

We consider signaling components, like a double phosphorylation cycle,having the ability to display bistability. The existence of more than onesteady state under particular biological conditions is strongly related to theexistence of positive feedback loops. If these components are connected toother signaling elements, they very likely undergo some sort of protein-proteininteraction. Many times, these interactions result in a non-explicit negativefeedback effect, leading to interlinked positive and negative feedbacks. Thiscombination was studied in the literature as a way to generate relaxation-typeoscillations. Here we show that the two feedbacks together ensure two types ofoscillations, the relaxation-type ones and a smoother type of oscillationsfunctioning in a very narrow range of frequencies. Even more, we show that thetwo feedbacks are essential for both oscillatory types to emerge, and it istheir hierarchy what determines the type of oscillation at work. We first studya double phosphorylation cycle with minimal additions that ensuresequestration. We identify two types of oscillatory behavior and a path in theparameter space connecting both of them, evidencing the change in feedbackhierarchies. Then, we apply a similar study to the first part of the MAPKcascade, finding similar results. Finally, we evaluate the performance of asimplified model that deals with a different bistable module.