Title :
Multistability of signal transduction motifs
Author :
Saez-Rodriguez, J. ; Hammerle-Fickinger, A. ; Dalal, O. ; Klamt, S. ; Gilles, E.D. ; Conradi, C.
Author_Institution :
Harvard Med. Sch., Boston, MA
fDate :
3/1/2008 12:00:00 AM
Abstract :
Protein domains are the basic units of signalling processes. The mechanisms they are involved in usually follow recurring patterns, such as phosphorylation/dephosphorylation cycles. A set of common motifs was defined and their dynamic models were analysed with respect to number and stability of steady states. In a first step, Feinberg´s chemical reaction network theory was used to determine whether a motif can show multistationarity or not. The analysis revealed that, apart from double-step activation motifs including a distributive mechanism, only those motifs involving an autocatalytic reaction can show multistationarity. To further characterise these motifs, a large number of randomly chosen parameter sets leading to bistability was generated, followed by a bifurcation analysis of each parameter set and a statistical evaluation of the results. The statistical results can be used to explore robustness against noise, pointing to the observation that multistationarity at the single-motif level may not be a robust property; the range of protein concentrations compatible with multistationarity is fairly narrow. Furthermore, experimental evidence suggests that protein concentrations vary substantially between cells. Considering a motif designed to be a bistable switch, this implies that fluctuation of protein concentrations between cells would prevent a significant proportion of motifs from acting as a switch. The authors consider this to be a first step towards a catalogue of fully characterised signalling modules.
Keywords :
bifurcation; cellular biophysics; proteins; Feinberg´s chemical reaction network theory; bifurcation analysis; dephosphorylation cycle; double-step activation motif; protein domains; signal transduction motifs multistability;
Journal_Title :
Systems Biology, IET
DOI :
10.1049/iet-syb:20070012