Trade-offs between tRNA abundance and mRNA secondary structure support smoothing of translation elongation rate.

Thomas E Gorochowski,Johannes A Roubos,Zoya Ignatova,Roel A.L Bovenberg

doi:10.1093/nar/gkv199

Thomas E Gorochowski, Johannes A Roubos + Show 2 more

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https://doi.org/10.1093/nar/gkv199

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Abstract

Translation of protein from mRNA is a complex multi-step process that occurs at a non-uniform rate. Variability in ribosome speed along an mRNA enables refinement of the proteome and plays a critical role in protein biogenesis. Detailed single protein studies have found both tRNA abundance and mRNA secondary structure as key modulators of translation elongation rate, but recent genome-wide ribosome profiling experiments have not observed significant influence of either on translation efficiency. Here we provide evidence that this results from an inherent trade-off between these factors. We find codons pairing to high-abundance tRNAs are preferentially used in regions of high secondary structure content, while codons read by significantly less abundant tRNAs are located in lowly structured regions. By considering long stretches of high and low mRNA secondary structure in Saccharomyces cerevisiae and Escherichia coli and comparing them to randomized-gene models and experimental expression data, we were able to distinguish clear selective pressures and increased protein expression for specific codon choices. The trade-off between secondary structure and tRNA-concentration based codon choice allows for compensation of their independent effects on translation, helping to smooth overall translational speed and reducing the chance of potentially detrimental points of excessively slow or fast ribosome movement.

Highlights

Translation of mRNAs into protein is crucial for cell viability and function and proceeds at a non-uniform rate along transcripts [1]
While much focus has been placed on the translation initiation step that is often rate limiting for endogenous genes [2,3], there is growing realization that the variable dynamics of translation elongation play a crucial role in both fine-tuning expression levels and ensuring the correct folding of soluble proteins [4,5,6]
To assess whether potential trade-offs are made between tRNA abundance and mRNA secondary structure, we first focused on S. cerevisiae for which experimental in vivo mRNA secondary structure measurements are available [32]

Summary

Introduction

Translation of mRNAs into protein is crucial for cell viability and function and proceeds at a non-uniform rate along transcripts [1]. While much focus has been placed on the translation initiation step that is often rate limiting for endogenous genes [2,3], there is growing realization that the variable dynamics of translation elongation play a crucial role in both fine-tuning expression levels and ensuring the correct folding of soluble proteins [4,5,6]. Synonymous codon usage strongly influences translational efficiency. Optimization of synonymous codon choice when designing recombinant genes, through minimization of rare codon use in the expression host, in many cases leads to significantly increased protein yields for mostly single-domain heterologous proteins [13,14]

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