Protein Scaffolds Can Enhance the Bistability of Multisite Phosphorylation Systems

Carlo Chan,Qing Nie,Xinfeng Liu,Germán Enciso,Liming Wang,Lee Bardwell

doi:10.1371/journal.pcbi.1002551

Abstract

The phosphorylation of a substrate at multiple sites is a common protein modification that can give rise to important structural and electrostatic changes. Scaffold proteins can enhance protein phosphorylation by facilitating an interaction between a protein kinase enzyme and its target substrate. In this work we consider a simple mathematical model of a scaffold protein and show that under specific conditions, the presence of the scaffold can substantially raise the likelihood that the resulting system will exhibit bistable behavior. This phenomenon is especially pronounced when the enzymatic reactions have sufficiently large KM, compared to the concentration of the target substrate. We also find for a closely related model that bistable systems tend to have a specific kinetic conformation. Using deficiency theory and other methods, we provide a number of necessary conditions for bistability, such as the presence of multiple phosphorylation sites and the dependence of the scaffold binding/unbinding rates on the number of phosphorylated sites.

Highlights

Protein phosphorylation is a ubiquitous form of post-translational modification [1]
We show that bistable behavior can be greatly enhanced by the presence of a scaffold protein, which binds to the substrate protein and either relocates it or otherwise affects the action of the modifying enzymes
The scaffold protein substantially widens the range of parameters for which bistability is observed whenKM, a key descriptor of enzymatic activity, assumes medium to large values found in a majority of enzymes

Summary

Introduction

Protein phosphorylation is a ubiquitous form of post-translational modification [1]. Since covalently-bound phosphate groups are strongly hydrophilic and negatively charged, they can activate or inhibit a protein by changing its conformation or the way it interacts with other proteins [2,3]. Phosphorylation is a key element of biological regulatory processes including signal transduction, gene regulation, the cell cycle, and protein degradation [4]. Multisite phosphorylation is a very common occurrence. Epidermal Growth Factor (EGF) receptor activation involves phosphorylation at multiple tyrosine residues by another EGF receptor [1]. Many proteins have a surprisingly large number of phosphorylation sites. Nine phosphorylation sites were identified in the cyclin-dependent kinase inhibitor Sic1 [5], more than 30 sites in EGF Receptor (EGFR) and several dozen in p53 [6]

Methods

Results

Discussion

Conclusion