TI - Discussion A new model for the intracellular signaling network . AB - The experiments by Vaknin and Berg on the effect of CheZ localization on the dose-response curves of E.coli[2] impose strong constraints on the design of a model of the intracellular chemotaxis network . These experiments unambiguously demonstrate that the second derivative of of CheZ wild-type cells is larger than that of CheZ mutant cells ( see Figure 1 ) . The topology of the intracellular chemotaxis network of the canonical model ( Equations 1-3 ) is such that the second derivative of must be equal to or smaller than zero : according to the canonical model the response curve cannot be convex . One way to fit the data is to assume that the response curve of CheZ wild-type cells is a straight line over the concentration range of interest , while of CheZ mutant cells is concave . The canonical model can yield such response curves . However , this scenario requires that in the CheZ mutant cells , some of the rate constants , such as the phosphatase activity , differ strongly from those in wild-type cells . Moreover , this would mean that CheZ mutant cells would adapt to a state in which is outside the working range of the motor . This scenario thus seems unlikely , although it cannot be ruled out . Here , we have presented two different models that can explain the FRET data of Vaknin and Berg [2] . In the first model , of CheZ wild-type cells is linear , while of CheZ mutant cells is strongly concave . The model is based on the in vitro observation that CheZ dePHOSphorylates CheYp in a cooperative manner [5] -[7] . The model leads over the relevant range of interest to fairly similar response curves for wild-type and mutant cells , and the non-stimulated state lies around 3 uM . This model , however , assumes that in wild-type cells all CheZ proteins are localized at the receptor cluster , while the data of Vaknin and Berg [2] suggest that in these cells only a fraction of about 10-20% is localized at the receptor cluster . We have therefore presented an alternative model that is consistent with most , if not all , of the currently available data . In this model , of CheZ wild-type cells is sigmoidal , while of CheZ mutant cells is hyperbolic . The model relies on the assumption that a small fraction of CheZ is localized at the receptor cluster , while the remainder freely diffuses in the cytoplasm ; moreover , it assumes that CheZ localized at the receptor cluster has both a higher binding affinity for CheYp and a higher catalytic activity than CheZ in the cytoplasm . All these assumptions seem to be supported by experiment [2] , [10] . In essence , the model that we propose consists of a push-pull network with one activating enzyme , CheA , and two deactivating enzymes , CheZ bound to the cluster and CheZ that freely diffuses in the cytoplasm . Our analysis shows that the competition between these two deactivating enzymes for binding and deactivating the SUBstrate can yield an ultrasensitive response even when the push-pull network does not operate in the zero-order regime . In fact , this mechanism of differential-affinity-and-catalytic-activity is evocative of the "branch point effect" , in which the interdependence of the activities of two branch-point enzymes that compete for a common SUBstrate can yield an abrupt change in the flux through one of the enzymes [24] . In the model proposed here , the spatial dependence of both the SUBstrate -binding affinity and catalytic activity of CheZ only acts to create two types of deactivating enzymes ; the proposed scheme could also work in a well-stirred model if one assumes that there exist two deactivating enzyme species .