Emergence and Enhancement of Ultrasensitivity through Posttranslational Modulation of Protein Stability.

Carla M Kumbale,Qiang Zhang,Eberhard O Voit

doi:10.3390/biom11111741

Carla M Kumbale, Qiang Zhang + Show 1 more

Open Access

https://doi.org/10.3390/biom11111741

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Journal: Biomolecules	Publication Date: Nov 22, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Georgia Institute of Technology, Emory University

Abstract

Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through the posttranslational modification (PTM) cycle of signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant, as by the classical Koshland–Goldbeter model. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here, we use mathematical models to explore the signal amplification properties in such scenarios and report some novel aspects. Our analyses indicate that PTM-induced protein stabilization brings the enzymes closer to saturation. As a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response, higher magnitude, and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Importantly, ultrasensitivity is not limited to modified or unmodified protein substrates—when protein turnover is considered, the total free protein substrate can also exhibit ultrasensitivity under several conditions. When full enzymatic reactions are used instead of Michaelis–Menten kinetics for the modeling, the total free protein substrate can even exhibit nonmonotonic dose–response patterns. It is conceivable that cells use inducible protein stabilization as a strategy in the signaling network to boost signal amplification while saving energy by keeping the protein substrate levels low at basal conditions.

Highlights

We examined whether changes in the synthesis of R can lead to ultrasensitivity when posttranslational modification (PTM) induces changes in protein stability
When the protein substrates in a covalent modification cycles (CMCs) are in excess relative to the modification or demodification enzymes, the degree of saturation of these enzymes depends on the Michaelis constants and the abundances of the contributing substrates
The covalent modification status of a protein substrate modulates its activity, but may alter its affinity as a substrate for the ubiquitination-proteasomal pathway that mediates the degradation of the majority of intracellular proteins [37]

Summary

Introduction

A well-studied example is the DNA damage response. Once the tumor suppressor p53 is phosphorylated by upstream kinases, such as ATM (ataxia telangiectasia mutated), in response to DNA double-strand breaks, its half-life increases dramatically from less than 30 min to over 3 h (Figure 1A), which causes the accumulation of p53 that can induce target gene expression [1,2]. A second example, in some sense of the opposite nature, occurs in the germinal center response of B lymphocytes. B cell receptor-activated MAPK phosphorylates BCL6 (B-cell lymphoma 6), resulting in accelerated degradation of BCL6 by the ubiquitin/proteasome pathway (Figure 1B), which helps the B cells exit the germinal center response [3].

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