The Design Principles of Biochemical Timers: Circuits that Discriminate between Transient and Sustained Stimulation

Many cellular responses for which timing is critical display temporal filtering-the ability to suppress response until stimulated for longer than a given minimal time. To identify biochemical circuits capable of kinetic filtering, we comprehensively searched the space of three-node enzymatic networks. We define a metric of "temporal ultrasensitivity," the steepness of activation as a function of stimulus duration. We identified five classes of core network motifs capable of temporal filtering, each with distinct functional properties such as rejecting high-frequency noise, committing to response (bistability), and distinguishing between long stimuli. Combinations of the two most robust motifs, double inhibition (DI) and positive feedback with AND logic (PF_AND), underlie several natural timer circuits involved in processes such as cell cycle transitions, T cell activation, and departure from the pluripotent state. The biochemical network motifs described in this study form a basis for understanding common ways cells make dynamic decisions.