Spatio-temporal correlations can drastically change the response of a MAPK pathway

TL;DR

This paper demonstrates that spatio-temporal correlations, especially rapid enzyme rebindings, can significantly alter the response of MAPK pathways, transforming their behavior from ultrasensitive and bistable to more linear responses.

Contribution

The study reveals how enzyme rebindings influence MAPK pathway responses, showing that spatial and temporal correlations can change the system's qualitative behavior.

Findings

Rapid enzyme rebindings speed up response times

Rebindings can eliminate ultrasensitivity and bistability

Slow ADP release preserves ultrasensitive responses

Abstract

Multisite covalent modification of proteins is omnipresent in eukaryotic cells. A well-known example is the mitogen-activated protein kinase (MAPK) cascade, where in each layer of the cascade a protein is phosphorylated at two sites. It has long been known that the response of a MAPK pathway strongly depends on whether the enzymes that modify the protein act processively or distributively: distributive mechanism, in which the enzyme molecules have to release the substrate molecules in between the modification of the two sites, can generate an ultrasensitive response and lead to hysteresis and bistability. We study by Green's Function Reaction Dynamics, a stochastic scheme that makes it possible to simulate biochemical networks at the particle level and in time and space, a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism. We find that the response of this network can differ dramatically from that predicted by a mean-field analysis based on the chemical rate equations. In particular, rapid rebindings of the enzyme molecules to the substrate molecules after modification of the first site can markedly speed up the response, and lead to loss of ultrasensitivity and bistability. In essence, rapid enzyme-substrate rebindings can turn a distributive mechanism into a processive mechanism. We argue that slow ADP release by the enzymes can protect the system against these rapid rebindings, thus enabling ultrasensitivity and bistability.