Sensitivity amplification in the phosphorylation-dephosphorylation cycle: nonequilibrium steady states, chemical master equation, and temporal cooperativity.
A new type of cooperativity termed temporal cooperativity [Biophys. Chem. 105, 585 (2003); Annu. Rev. Phys. Chem. 58, 113 (2007)] emerges in the signal transduction module of phosphorylation-dephosphorylation cycle (PdPC). It utilizes multiple kinetic cycles in time, in contrast to allosteric cooperativity that utilizes multiple subunits in a protein. In the present paper, we thoroughly investigate both the deterministic (microscopic) and stochastic (mesoscopic) models and focus on the identification of the source of temporal cooperativity via comparing with allosteric cooperativity. A thermodynamic analysis confirms again the claim that the chemical equilibrium state exists if and only if the phosphorylation potential DeltaG=0, in which case the amplification of sensitivity is completely abolished. Then we provide comprehensive theoretical and numerical analysis with the first-order and zero-order assumptions in PdPC, respectively. Furthermore, it is interestingly found that the underlying mathematics of temporal cooperativity and allosteric cooperativity are equivalent, and both of them can be expressed by "dissociation constants," which also characterizes the essential differences between the simple and ultrasensitive PdPC switches. Nevertheless, the degree of allosteric cooperativity is restricted by the total number of sites in a single enzyme molecule that cannot be freely regulated, while temporal cooperativity is only restricted by the total number of molecules of the target protein that can be regulated in a wide range and gives rise to the ultrasensitivity phenomenon.
Ge
Hao
H
LMAM, School of Mathematical Sciences, Peking University, Beijing 100871, People's Republic of China. edmund_ge@tom.com
Qian
Min
M
D007700:Kinetics; D008956:Models, Chemical; D010766:Phosphorylation; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013269:Stochastic Processes; D013816:Thermodynamics