Emergence of biological oscillationscombining compartmentalization and sequestration in cell signaling

HERNAN GRECCO; ALEJANDRA C VENTURA; ALAN GIVRE

Buenos Aires

Conferencia; ISCB Latin America Bioinformatics Conference; 2016

ISCB

Background:Information processing is a key event in life. A recurrent structure inbiochemical networks involved in information processing is an activationdeactivationcycle, involving two states of a same protein: a protein isactivated by the incorporation of a chemical group and deactivated by itsremoval, where ?active? means that the protein can make some specifictask. Biochemical networks involve cascading of these structures, whereeach activated protein becomes the activator of another similar cycle.In this work we consider a single cycle in which the different componentsshuttle in and out of a cellular compartment (e.g the nucleus), where theymeet again and undergo the same cycle. The activated protein inside thecompartment acts over a cellular target, being sequestered by this target ina simple binding reaction. This simple and generic signaling circuit is arecurrent structure in many signaling pathways.It was recently shown that compartmentalization of an activationinactivationcycle can lead to bistability, an emergent behavior that is notpossible to obtain without the addition of a positive feedback regulationover 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 anegative feedback effect over an activation-deactivation cycle, somethingthat has been named implicit negative feedback or hidden feedback.Results:We reasoned that in the mentioned signaling circuit, a cycle that shuttles inand out of a cellular compartment where it activates a target thus receivingan (implicit) negative feedback from this activation, bistability andnegative feedback would be coexisting. From a dynamical systems point ofview and with the right choice of the involved time-scales, thiscombination could lead to oscillations. An oscillatory regime would beguided by a van der Pol oscillator, which is based on a combination of afast bistable system and a slow variable that switches the system betweenbranches of two alternative stablesteady states.We proved this hypothesis by a combined theoretical-computational andstatistical approach. We characterized the different signaling regimes thatthe mentioned circuit can exhibit and explored the occurrence of theseregimes over the parameter space. Our results highlight a new mechanismto explain the emergence of oscillations that does not require those usuallyinvoked (time delay, explicit negative feedback).Conclusions:The signaling structure that was characterized is ubiquitous in cellsignaling pathways, so an oscillatory regime is at hand for them and couldbe obtained by the right tuning of some key parameters. This mechanismmay be the underlying mechanism for many biological clocks, and mightbe generalizable for other systems.Supported by: CONICET, Foncyt.