Enzyme Localization Can Drastically Affect Signal Amplification in Signal Transduction Pathways

Siebe B Van Albada,Pieter Rein Ten Wolde,Christopher V Rao

doi:10.1371/journal.pcbi.0030195

Siebe B Van Albada, Pieter Rein Ten Wolde + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.0030195

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Abstract

Push–pull networks are ubiquitous in signal transduction pathways in both prokaryotic and eukaryotic cells. They allow cells to strongly amplify signals via the mechanism of zero-order ultrasensitivity. In a push–pull network, two antagonistic enzymes control the activity of a protein by covalent modification. These enzymes are often uniformly distributed in the cytoplasm. They can, however, also be colocalized in space; for instance, near the pole of the cell. Moreover, it is increasingly recognized that these enzymes can also be spatially separated, leading to gradients of the active form of the messenger protein. Here, we investigate the consequences of the spatial distributions of the enzymes for the amplification properties of push–pull networks. Our calculations reveal that enzyme localization by itself can have a dramatic effect on the gain. The gain is maximized when the two enzymes are either uniformly distributed or colocalized in one region in the cell. Depending on the diffusion constants, however, the sharpness of the response can be strongly reduced when the enzymes are spatially separated. We discuss how our predictions could be tested experimentally.

Highlights

While it has long been assumed that the enzymes are uniformly distributed in the cytoplasm, it is increasingly becoming clear that in many systems one or both of the enzymes are localized in space, for instance near the cell pole
We study by numerical calculations how the amplification properties of push–pull networks depend upon the spatial distribution of the enzymes
Our analysis reveals that the spatial distribution of the enzymes can have a dramatic effect on the capacity of push–pull networks to amplify input signals: the maximum gain of the network in which one enzyme is localized at one end of the cell, while the other is not, can be much lower than that of the network in which the components are uniformly distributed in space

Summary

Introduction

To this end, cells can employ a variety of amplification mechanisms. Signals can be amplified via positive feedback, cooperative binding of signaling molecules to receptors, or interactions between receptor molecules [1] Another principal mechanism for signal amplification is zeroorder ultrasensitivity [2,3]. One well-known example is a network in which a kinase phosphorylates a component, and a phosphatase dephosphorylates the same component If both enzymes operate near saturation, the modification reactions become zero order, which means that the reaction rates become insensitive to the substrate concentrations. The amplification properties of push–pull networks have been analyzed in detail [2,3,4,5,6,7,8] In these studies, it is assumed that the antagonistic enzymes are uniformly distributed in space.

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