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

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 tha...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 107; no. 3; pp. 1247 - 1252
Main Authors Lipshtat, Azi, Jayaraman, Gomathi, He, John Cijiang, Iyengar, Ravi
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 19.01.2010
National Acad Sciences
Subjects
Biochemistry
Biological Sciences
Cells
Enzyme kinetics
Fermions
GTP Phosphohydrolases - metabolism
Guanine nucleotide dissociation inhibitors
Kinetics
Mathematical functions
Molecules
Physiological regulation
Proteins
Reaction kinetics
Receptor, Cannabinoid, CB1 - metabolism
Receptors
Signal Transduction
T lymphocytes
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Summary: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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Author contributions: A.L conducted all the theoretical analysis; A.L., J.C.H., and R.I. designed research; G.J. and J.C.H. performed experiments; and A.L. and R.I. wrote the paper.
Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved November 11, 2009 (received for review August 3, 2009)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0908647107