title: Bistability by multiple phosphorylation of regulatory proteins.
abstract: The activity of a protein can be reversibly modulated by post-translational, covalent modifications, such as phosphorylation and dephosphorylation. In many cases, the modulated protein may be phosphorylated by the same kinase on many different amino acid residues. Such multisite phosphorylations may occur progressively (during a single binding event of kinase to substrate) or distributively (the kinase dissociates from its substrate after each phosphorylation reaction). If a protein is phosphorylated by a distributive multisite mechanism, then the net activity of a population of these protein molecules can be a highly nonlinear function of the ratio of activities of the kinase and phosphatase enzymes. If the multiply phosphorylated protein is embedded in a positive feedback loop with its kinase and/or phosphatase, then the network may exhibit robust bistable behavior. Using numerical simulations and bifurcation theory, we study the properties of a particular bistable reaction network motivated by the antagonistic relationship between cyclin-dependent kinase and its multiply phosphorylated target, Cdh1, which is involved in the degradation of cyclin molecules. We characterize the bistable switch in terms of (i) the mechanism of distributive phosphorylation (ordered or disordered), (ii) the number of phosphorylation sites on the target protein, (iii) the effect of phosphorylation on the target protein (abrupt or progressive inactivation), and (iv) the effects of stochastic fluctuations in small cells with limited numbers of kinase, phosphatase and target proteins.
authors.affiliation: Oxford Centre for Integrative Systems Biology, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kapuy
authors.forename: Debashis
authors.initials: D
authors.lastname: Barik
authors.forename: Maria Rosa Domingo
authors.initials: MR
authors.lastname: Sananes
authors.forename: John J
authors.initials: JJ
authors.lastname: Tyson
authors.forename: Béla
authors.initials: B
authors.lastname: Novák
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D008954:Models, Biological; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D013269:Stochastic Processes
chemical_list: D011506:Proteins