Emergence of biological oscillations combining compartmentalization and sequestration in cell signaling

ALAN GIVRE; HERNAN GRECCO; ALEJANDRA C VENTURA

Buenos Aires

Conferencia; Frontiers in Physical Sciences; 2016

ICAS

Abstract:Background. Information processing is a key event in life. A recurrent structure in biochemicalnetworks involved in information processing is an activation-deactivation cycle, involving twostates of a same protein: a protein is activated by the incorporation of a chemical group anddeactivated by its removal, where ?active? means that the protein can make some specific task.Biochemical networks involve cascading of these structures, where each activated proteinbecomes the activator of another similar cycle.In this work we consider a single cycle in which the different components shuttle in and out of acellular compartment (e.g the nucleus), where they meet again and undergo the same cycle.The activated protein inside the compartment acts over a cellular target, being sequestered bythis target in a simple binding reaction. This simple and generic signaling circuit is a recurrentstructure in many signaling pathways.It was recently shown that compartmentalization of an activation-inactivation cycle can lead tobistability, an emergent behavior that is not possible to obtain without the addition of a positivefeedback regulation over the cycle. The presence of a compartment generates this positivefeedback loop in a non-obvious way leading to the mentioned behavior.It was also shown that sequestration by binding reactions generates a negative feedback effectover an activation-deactivation cycle, something that has been named implicit negativefeedback or hidden feedback.Results. We reasoned that in the mentioned signaling circuit, a cycle that shuttles in and out ofa cellular compartment where it activates a target thus receiving an (implicit) negative feedbackfrom this activation, bistability and negative feedback would be coexisting. From a dynamicalsystems point of view and with the right choice of the involved time-scales, this combinationcould lead to oscillations. An oscillatory regime would be guided by a van der Pol oscillator,which is based on a combination of a fast bistable system and a slow variable that switches thesystem between branches of two alternative stable steady states.We proved this hypothesis by a combined theoretical-computational and statistical approach.We characterized the different signaling regimes that the mentioned circuit can exhibit andexplored the occurrence of these regimes over the parameter space. Our results highlight a newmechanism to explain the emergence of oscillations that does not require those usually invoked(time delay, explicit negative feedback).Conclusions. The signaling structure that was characterized is ubiquitous in cell signalingpathways, so an oscillatory regime is at hand for them and could be obtained by the right tuningof some key parameters. This mechanism may be the underlying mechanism for manybiological clocks, and might be generalizable for other systems.