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Updated: Jul 20, 2026
Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
Oscillatory dynamics arising from competitive inhibition and multisite phosphorylation
Vijay Chickarmane1, Boris N Kholodenko, Herbert M Sauro
1Keck Graduate Institute, 535 Watson Dr, Claremont, CA 91711, USA. Vijay_Chickarmane@kgi.edu <Vijay_Chickarmane@kgi.edu>
Abstract:
There have been a growing number of observations of oscillating protein levels (p53 and NFkB) in eukaryotic signalling pathways. This has resulted in a renewed interest in the mechanism by which such oscillations might occur. Recent computational work has shown that a multisite phosphorylation mechanism such as that found in the MAPK cascade can theoretically exhibit bistability. The bistable behavior was shown to arise from sequestration and saturation mechanisms for the enzymes that catalyse the multisite phosphorylation cycle. These effects generate the positive feedback necessary for bistability. In this paper we describe two kinds of oscillatory dynamics which can occur in a network by which, both use such bistable multisite phosphorylated cycles. In the first example, the fully phosphorylated form of the phosphorylated cycle represses the production of the kinase, which carries out the phosphorylation of the unphosphorylated states of the cycle. The dynamics of this system leads to a relaxation oscillator. In the second example, we consider a cascade of two cycles, in which the fully phosphorylated form of the kinase, in the first cycle, phosphorylates the unphosphorylated forms in the second cycle. A feedback loop, by which the fully phosphorylated form of the second cycle inhibits the kinase step in the first cycle is also present. In this case we obtain a ring oscillator. Both these networks illustrate the versatility of the multisite bistable network.
Insights
This study explores how multisite phosphorylation cycles generate bistability, leading to protein oscillations in eukaryotic signaling pathways. Two models demonstrate relaxation and ring oscillators, highlighting network versatility.
Area of Science:
- Biochemistry
- Systems Biology
- Computational Biology
Background:
- Growing observations of oscillating protein levels (e.g., p53, NFkB) in eukaryotic signaling pathways.
- Renewed interest in the mechanisms underlying these biological oscillations.
- Previous computational work suggests multisite phosphorylation can exhibit bistability.
Purpose of the Study:
- To investigate oscillatory dynamics arising from bistable multisite phosphorylation cycles.
- To describe two distinct network architectures that generate such oscillations.
- To illustrate the versatility of bistable multisite phosphorylation networks.
Main Methods:
- Theoretical modeling of multisite phosphorylation cycles.
- Analysis of network dynamics incorporating sequestration and saturation mechanisms.
- Simulation of two specific network designs: a repression-based relaxation oscillator and a two-cycle ring oscillator.
Main Results:
- Demonstrated that multisite phosphorylation cycles can exhibit bistability due to enzyme sequestration and saturation.
- Characterized a relaxation oscillator where phosphorylated protein represses kinase production.
- Characterized a ring oscillator in a two-cycle cascade with feedback inhibition.
Conclusions:
- Bistable multisite phosphorylation networks provide a versatile mechanism for generating biological oscillations.
- The described network models offer insights into the dynamics of signaling pathways with oscillating proteins.
- These findings contribute to understanding the fundamental principles of biological network behavior.
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