Frequency-preference response in covalent modification cycles under substrate sequestration conditions

Juliana Reves Szemere,Horacio G Rotstein,Alejandra C Ventura

doi:10.1038/s41540-021-00192-8

Abstract

Covalent modification cycles (CMCs) are basic units of signaling systems and their properties are well understood. However, their behavior has been mostly characterized in situations where the substrate is in excess over the modifying enzymes. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations, leading to substrate sequestration by the enzymes. In this enzyme-in-excess regime, CMCs have been shown to exhibit signal termination, the ability of the product to return to a stationary value lower than its peak in response to constant stimulation, while this stimulation is still active, with possible implications for the ability of systems to adapt to environmental inputs. We characterize the conditions leading to signal termination in CMCs in the enzyme-in-excess regime. We also demonstrate that this behavior leads to a preferred frequency response (band-pass filters) when the cycle is subjected to periodic stimulation, whereas the literature reports that CMCs investigated so far behave as low-pass filters. We characterize the relationship between signal termination and the preferred frequency response to periodic inputs and we explore the dynamic mechanism underlying these phenomena. Finally, we describe how the behavior of CMCs is reflected in similar types of responses in the cascades of which they are part. Evidence of protein abundance in vivo shows that enzymes and substrates are present in comparable concentrations, thus suggesting that signal termination and frequency-preference response to periodic inputs are also important dynamic features of cell signaling systems, which have been overlooked.

Highlights

Biological systems must respond to internal and external variations such as the depletion of nutrients, the fluctuations in hormone levels, and the arrival of sensory signals
We emphasize that a cascade is not a feedforward network where CMC2 responds to the output from CMC1, but it is an interconnected network where CMC2 affects CMC1 and knowledge from the CMC1 output is not enough to predict the CMC2 output
Step-constant stimulation serves the dual purpose of characterizing the variety of steady states available to Covalent modification cycles (CMCs) and uncovering the transient dynamics leading to these states

Summary

Introduction

Biological systems must respond to internal and external variations such as the depletion of nutrients, the fluctuations in hormone levels, and the arrival of sensory signals. Covalent modification cycles (CMCs) are one of the major intracellular signaling mechanisms, both in prokaryotic and eukaryotic organisms[2]. In such cycles, a signaling protein is modified by the addition of a chemical group. A signaling protein is modified by the addition of a chemical group This modification may result in either activation or inactivation, depending on the particular signaling pathway involved, followed by a reverse process, closing the cycle. External stimuli that produce a change in the enzymatic activity shift the activation state of the target protein, creating a departure from a steady state, which can propagate through a signaling cascade. While individual CMCs are elements of a large signaling network, understanding their response to inputs is an essential first step in characterizing the response of more-elaborated signaling networks to external stimuli

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