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Cell Syst. 2019 Sep 25;9(3):297-308.e2. doi: 10.1016/j.cels.2019.07.008. Epub 2019 Sep 11.

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

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; Cell Design Initiative, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: wendell.lim@ucsf.edu.

Abstract

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 (PFAND), 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.

KEYWORDS:

biochemical circuits; kinetic filtering; networks; signal transduction

PMID:
31521602
PMCID:
PMC6763348
[Available on 2020-09-25]
DOI:
10.1016/j.cels.2019.07.008

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