Compact modeling of allosteric multisite proteins: application to a cell size checkpoint.

Germán Enciso,Douglas R Kellogg,Arturo Vargas

doi:10.1371/journal.pcbi.1003443

Germán Enciso, Douglas R Kellogg + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.1003443

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Abstract

We explore a framework to model the dose response of allosteric multisite phosphorylation proteins using a single auxiliary variable. This reduction can closely replicate the steady state behavior of detailed multisite systems such as the Monod-Wyman-Changeux allosteric model or rule-based models. Optimal ultrasensitivity is obtained when the activation of an allosteric protein by its individual sites is concerted and redundant. The reduction makes this framework useful for modeling and analyzing biochemical systems in practical applications, where several multisite proteins may interact simultaneously. As an application we analyze a newly discovered checkpoint signaling pathway in budding yeast, which has been proposed to measure cell growth by monitoring signals generated at sites of plasma membrane growth. We show that the known components of this pathway can form a robust hysteretic switch. In particular, this system incorporates a signal proportional to bud growth or size, a mechanism to read the signal, and an all-or-none response triggered only when the signal reaches a threshold indicating that sufficient growth has occurred.

Highlights

Protein phosphorylation is a common form of post-translational modification frequently used in nature to alter protein activity, for instance by changing the electrostatic properties of the protein or its spatial structure
Many multisite proteins are involved in regulatory processes that can benefit from the presence of bistability, hysteresis, or limit cycles, which require sufficiently nonlinear interactions in addition to the right type of feedback [7,8]
A reasonable hypothesis is that multisite phosphorylation can give rise to ultrasensitive dose responses, in a way that would not be possible in a comparable single-site system [9,10,11,12,13]

Summary

Introduction

Protein phosphorylation is a common form of post-translational modification frequently used in nature to alter protein activity, for instance by changing the electrostatic properties of the protein or its spatial structure. The differences in the function of single-site vs multisite phosphorylation are not completely understood. Cell size checkpoints should translate growth into a proportional checkpoint signal. They should read the signal to detect when it reaches a threshold that indicates when sufficient growth has occurred. When the threshold is reached the checkpoint should trigger a switch-like cell cycle transition. All of these mechanisms should be robust and adaptable to function in cells of diverse size and shape, and under conditions of fluctuating growth rates

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