Multistability of signal transduction motifs.
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.
Saez-Rodriguez
J
J
Harvard Medical School, Boston, MA 02115, USA. julio@hms.harvard.edu
Hammerle-Fickinger
A
A
Dalal
O
O
Klamt
S
S
Gilles
E D
ED
Conradi
C
C
D020816:Amino Acid Motifs / Q000502:physiology; D003627:Data Interpretation, Statistical; D030562:Databases, Protein; D025461:Feedback, Physiological; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D025941:Protein Interaction Mapping / Q000379:methods; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods