Rate-Limiting Steps in Yeast Protein Translation

Summary

Deep sequencing now provides detailed snapshots of ribosome occupancy on mRNAs. We leverage these data to parameterize a computational model of translation, keeping track of every ribosome, tRNA, and mRNA molecule in a yeast cell. We determine the parameter regimes in which fast initiation or high codon bias in a transgene increases protein yield and infer the initiation rates of endogenous Saccharomyces cerevisiae genes, which vary by several orders of magnitude and correlate with 5′ mRNA folding energies. Our model recapitulates the previously reported 5′-to-3′ ramp of decreasing ribosome densities, although our analysis shows that this ramp is caused by rapid initiation of short genes rather than slow codons at the start of transcripts. We conclude that protein production in healthy yeast cells is typically limited by the availability of free ribosomes, whereas protein production under periods of stress can sometimes be rescued by reducing initiation or elongation rates.

Graphical Abstract

Highlights

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  Computational model of translation tracks all ribosomes, tRNAs, and mRNAs in a cell

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  Translation is generally limited by initiation, not elongation

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  Model allows inference of initiation rates for all yeast genes

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  Ramp of 5′ ribosomes is caused by rapid initiation of short genes

Abstract

A computational model for translation in yeast quantifies translation dynamics for an entire cell and suggests that both basal and conditional expression levels are governed by availability of free ribosomes.