Adaptation for Protein Synthesis Efficiency in a Naturally Occurring Self-Regulating Operon

Dorota Herman,Dov J Stekel,Christopher M Thomas,Mark Isalan

doi:10.1371/journal.pone.0049678

Abstract

The korAB operon in RK2 plasmids is a beautiful natural example of a negatively and cooperatively self-regulating operon. It has been particularly well characterized both experimentally and with mathematical models. We have carried out a detailed investigation of the role of the regulatory mechanism using a biologically grounded mechanistic multi-scale stochastic model that includes plasmid gene regulation and replication in the context of host growth and cell division. We use the model to compare four hypotheses for the action of the regulatory mechanism: increased robustness to extrinsic factors, decreased protein fluctuations, faster response-time of the operon and reduced host burden through improved efficiency of protein production. We find that the strongest impact of all elements of the regulatory architecture is on improving the efficiency of protein synthesis by reduction in the number of mRNA molecules needed to be produced, leading to a greater than ten-fold reduction in host energy required to express these plasmid proteins. A smaller but still significant role is seen for speeding response times, but this is not materially improved by the cooperativity. The self-regulating mechanisms have the least impact on protein fluctuations and robustness. While reduction of host burden is evident in a plasmid context, negative self-regulation is a widely seen motif for chromosomal genes. We propose that an important evolutionary driver for negatively self-regulated genes is to improve the efficiency of protein synthesis.

Highlights

Negative self-regulation of transcription is commonly seen for transcription factors in many species and has been identified as a ‘network motif’ [1]
Note the synthesis rates kA and kB are parameters that represent an amalgamation of all processes involved in protein synthesis, including transcription, translation and mRNA turn-over, so the different systems are robust to changes in rates of any of these processes
The model comparisons for protein fluctuations, response times and mRNA usage are shown in Figure 3; the results are broadly similar to those described above, demonstrating that these are robust to uncertainty in parameter values

Summary

Introduction

Negative self-regulation of transcription is commonly seen for transcription factors in many species and has been identified as a ‘network motif’ [1]. Others have shown that negative self-regulation can improve the trade-offs between these objectives, for example noise reduction and speed [7]. These hypotheses have generally been explored either with generic theoretical models [2] [8] or with synthetic systems [9], often using either parameter values or experimental conditions that do not reflect the in vivo operational context of these systems

Methods

Results

Conclusion