Design of versatile biochemical switches that respond to amplitude, duration, and spatial cues

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2010; 107(3):1247-52. DOI: 10.1073/pnas.0908647107
Source: PubMed


Cells often mount ultrasensitive (switch-like) responses to stimuli. The design principles underlying many switches are not known. We computationally studied the switching behavior of GTPases, and found that this first-order kinetic system can show ultrasensitivity. Analytical solutions indicate that ultrasensitive first-order reactions can yield switches that respond to signal amplitude or duration. The three-component GTPase system is analogous to the physical fermion gas. This analogy allows for an analytical understanding of the functional capabilities of first-order ultrasensitive systems. Experiments show amplitude- and time-dependent Rap GTPase switching in response to Cannabinoid-1 receptor signal. This first-order switch arises from relative reaction rates and the concentrations ratios of the activator and deactivator of Rap. First-order ultrasensitivity is applicable to many systems where threshold for transition between states is dependent on the duration, amplitude, or location of a distal signal. We conclude that the emergence of ultrasensitivity from coupled first-order reactions provides a versatile mechanism for the design of biochemical switches.

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