Abstract
Multisite protein phosphorylation plays a prominent role in intracellular processes like signal transduction, cell-cycle control and nuclear signal integration. Many proteins are phosphorylated in a sequential and distributive way at more than one phosphorylation site. Mathematical models of \(n\)-site sequential distributive phosphorylation are therefore studied frequently. In particular, in Wang and Sontag (J Math Biol 57:29–52, 2008), it is shown that models of \(n\)-site sequential distributive phosphorylation admit at most \(2n-1\) steady states. Wang and Sontag furthermore conjecture that for odd \(n\), there are at most \(n\) and that, for even \(n\), there are at most \(n+1\) steady states. This, however, is not true: building on earlier work in Holstein et al. (Bull Math Biol 75(11):2028–2058, 2013), we present a scalar determining equation for multistationarity which will lead to parameter values where a \(3\)-site system has \(5\) steady states and parameter values where a \(4\)-site system has \(7\) steady states. Our results therefore are counterexamples to the conjecture of Wang and Sontag. We furthermore study the inherent geometric properties of multistationarity in \(n\)-site sequential distributive phosphorylation: the complete vector of steady state ratios is determined by the steady state ratios of free enzymes and unphosphorylated protein and there exists a linear relationship between steady state ratios of phosphorylated protein.
Similar content being viewed by others
References
Conradi C, Flockerzi D (2012) Multistationarity in mass action networks with applications to ERK activation. J Math Biol 65(1):107–156
Conradi C, Flockerzi D, Raisch J (2008) Multistationarity in the activation of an MAPK: parametrizing the relevant region in parameter space. Math Biosci 211(1):105–131
Conradi C, Mincheva M (2014) Catalytic constants enable the emergence of bistability in dual phosphorylation. J R Soc Interface 11(95):20140158
Enciso G, Kellogg D, Vargas A (2014) Compact modeling of allosteric multisite proteins: application to a cell size checkpoint. PLoS Comput Biol 10(2):e1003443
Feliu E, Wiuf C (2012) Enzyme-sharing as a cause of multi-stationarity in signalling systems. J R Soc Interface 9(71):1224–1232
Gunawardena J (2005) Multisite protein phosphorylation makes a good threshold but can be a poor switch. Proc Natl Acad Sci USA 102(41):14617–14622
Gunawardena J (2007) Distributivity and processivity in multisite phosphorylation can be distinguished through steady-state invariants. Biophys J 93(11):3828–3834
Holstein K, Flockerzi D, Conradi C (2013) Multistationarity in sequential distributed multisite phosphorylation networks. Bull Math Biol 75(11):2028–2058
Karp R, Pérez Millán M, Dasgupta T, Dickenstein A, Gunawardena J (2012) Complex-linear invariants of biochemical networks. J Theor Biol 311:130–138
Kumar M, Gunawardena J (2008) The geometry of multisite phosphorylation. Biophys J 95(12):5533–5543
Markevich N, Hoek, Kholodenko B (2004) Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascades. J Cell Biol 164(3):353–359
Pérez Millán M, Dickenstein A, Shiu A, Conradi C (2012) Chemical reaction systems with toric steady states. Bull Math Biol 74:1027–1065
Ryerson S, Enciso G (2013) Ultrasensitivity in independent multisite systems. J Math Biol. doi:10.1007/s00285-013-0727-x
Salazar C, Höfer T (2007) Versatile regulation of multisite protein phosphorylation by the order of phosphate processing and protein-protein interactions. FEBS J 274:1046–1061
Salazar C, Höfer T (2009) Multisite protein phosphorylation—from molecular mechanisms to kinetic models. FEBS J 276(12):3177–3198
Thomas R, Kaufman M (2001) Multistationarity, the basis of cell differentiation and memory. I. structural conditions of multistationarity and other nontrivial behavior. Chaos 11(1):170–179
Thomas R, Kaufman M (2001) Multistationarity, the basis of cell differentiation and memory. II. Logical analysis of regulatory networks in terms of feedback circuits. Chaos 11(1):180–195
Thomson M., Gunawardena J. (2007) Multi-bit information storage by multisite phosphorylation. arXiv:0706.3735
Thomson M, Gunawardena J (2009) The rational parameterisation theorem for multisite post-translational modification systems. J Theor Biol 261(4):626–636
Thomson M, Gunawardena J (2009) Unlimited multistability in multisite phosphorylation systems. Nature 460(7252):274–277
Wang L, Sontag E (2008) On the number of steady states in a multiple futile cycle. J Math Biol 57:29–52
Author information
Authors and Affiliations
Corresponding author
Appendix: The Network Matrices for \(n\ge 2\)
Appendix: The Network Matrices for \(n\ge 2\)
The matrices \({\mathcal {Y}}\), \(Z\), \(E\) and \(L\) can be obtained from Eqs. (7), (8), (9) and (10) of this manuscript. We recall the definition of the stoichiometric matrix \(S\) from Sect. 3 of Holstein et al. (2013). With the following sub-matrices
of dimension \(3\times 6\), one has
For the convenience of the reader, we close this appendix with the data for \(n=3\):
Rights and permissions
About this article
Cite this article
Flockerzi, D., Holstein, K. & Conradi, C. N-site Phosphorylation Systems with 2N-1 Steady States. Bull Math Biol 76, 1892–1916 (2014). https://doi.org/10.1007/s11538-014-9984-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11538-014-9984-0