Frequency preference in covalent modification cycles under sequestration conditions

HORACIO G ROTSTEIN; ALEJANDRA C VENTURA; JULIANA REVES SZEMERE

Puerto Madryn

Workshop; Workshop Statistical physics in biological networks; 2020

General Sarmiento National University

Covalent modification cycles (CMCs) are basic units of signaling systemsand their properties are well understood. However, the behavior of such systemshas been mostly characterized in situations where the modifying enzymes aresaturated by the substrate. Experimental data on protein abundance suggest thatthe enzymes and their target proteins are present in comparable concentrations,leading to a different scenario in which the substrate is mostly sequestered bythe enzymes. Related to this last condition, a type of response called signaltermination was proposed in the literature, in which the modified substrate ofthe CMC is formed only for a certain amount of time, producing a transientresponse in the cycle. We here characterize the conditions leading to signaltermination under constant stimulation in CMCs. In addition, we demonstratethat this behavior leads to a frequency preference when the cycle is subjectedto periodic stimulation ,while the literature reports that CMCs behave as lowpass filters. Altogether, signal termination and frequency preference are twoimportant features in cell signaling that were overlooked in the literatureassociated to CMC. The evidence that, in conditions mimicking an in vivo scenario, enzymes and substratesare present in comparable concentrations suggests that these two properties maybe ubiquitous in cell signaling systems.