Dataset Information

Thomson2009 – Unlimited multistability in multisite phosphorylation systems

ABSTRACT: This model describes a distributive, sequential system with n = 4, which is a simplified example of unlimited multistability in multisite phosphorylation systems. This method can be applied to systems with multiple substrates and enzymes. This model is described in the article: Unlimited multistability in multisite phosphorylation systems. Thomson, Matthew & Gunawardena, Jeremy. (2009). Nature. 460. 274-7. 10.1038/nature08102 (https://www.nature.com/articles/nature08102). Antimony and Tellurium used. Figure 2 of the reference publication has been reproduced. The code files are available on Github (https://github.com/SunnyXu/Unlimited_multistability). The simulation was performed using Spyder for Tellurium 3.7 (http://tellurium.analogmachine.org/).

SUBMITTER: Jin Xu

PROVIDER: MODEL2002110001 | BioModels | 2020-02-12

REPOSITORIES: BioModels

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	MODEL2002110001?filename=Fig2-a.py	Other
	MODEL2002110001?filename=Fig2-b.py	Other
	MODEL2002110001?filename=Fig2a-1.pdf	Pdf
	MODEL2002110001?filename=Fig2a-2.pdf	Pdf
	MODEL2002110001?filename=Fig2b.pdf	Pdf

Items per page:

1 - 5 of 7

Publications

Unlimited multistability in multisite phosphorylation systems.

Thomson Matthew M Gunawardena Jeremy J

Nature 20090617 7252

Reversible phosphorylation on serine, threonine and tyrosine is the most widely studied posttranslational modification of proteins. The number of phosphorylated sites on a protein (n) shows a significant increase from prokaryotes, with n </= 7 sites, to eukaryotes, with examples having n >/= 150 sites. Multisite phosphorylation has many roles and site conservation indicates that increasing numbers of sites cannot be due merely to promiscuous phosphorylation. A substrate with n sites has an expon ...[more]

PMID: 19536158

Similar Datasets

Project description:Markevich2004 - MAPK double phosphorylation, ordered Michaelis-Menton The model corresponds to the schemas 1 and 2 of Markevich et al 2004, as described in the figure 1 and modelled using Michaelis-Menten like kinetics. Phosphorylations and dephosphorylations follow distributive ordered kinetics. It reproduces figure 3 of the main article. This model is described in the article: Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. Markevich NI, Hoek JB, Kholodenko BN. J. Cell Biol. 2004 Feb; 164(3): 353-359 Abstract: Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity. This model is hosted on BioModels Database and identified by: BIOMD0000000027. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:The model corresponds to the schema 3 of Markevich et al 2004, as described in the figure 2 and the supplementary table S2. Phosphorylations follow distributive random kinetics, while dephosphorylations follow an ordered mechanism. The phosphorylations are modeled with three elementary reactions: E+SES->E+P The dephosphorylations are modeled with five elementary reactions: E+SES->EPE+P The model reproduces figure 5 in the main article. The model is further described in: Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. Markevich NI, Hoek JB, Kholodenko BN. J Cell Biol. 2004 Feb 2;164(3):353-9. PMID: 14744999 ; DOI: 10.1083/jcb.200308060 Abstract: Mitogen-activated protein kinase (MAPK) cascades can operate as bistable switches residing in either of two different stable states. MAPK cascades are often embedded in positive feedback loops, which are considered to be a prerequisite for bistable behavior. Here we demonstrate that in the absence of any imposed feedback regulation, bistability and hysteresis can arise solely from a distributive kinetic mechanism of the two-site MAPK phosphorylation and dephosphorylation. Importantly, the reported kinetic properties of the kinase (MEK) and phosphatase (MKP3) of extracellular signal-regulated kinase (ERK) fulfill the essential requirements for generating a bistable switch at a single MAPK cascade level. Likewise, a cycle where multisite phosphorylations are performed by different kinases, but dephosphorylation reactions are catalyzed by the same phosphatase, can also exhibit bistability and hysteresis. Hence, bistability induced by multisite covalent modification may be a widespread mechanism of the control of protein activity. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team. For more information see the terms of use . To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Ortega2006 - bistability from double phosphorylation in signal transduction This model is described in the article: Bistability from double phosphorylation in signal transduction. Kinetic and structural requirements. Ortega F, Garcés JL, Mas F, Kholodenko BN, Cascante M. FEBS J. 2006 Sep; 273(17): 3915-3926 Abstract: Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins. This model is hosted on BioModels Database and identified by: BIOMD0000000258. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.