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Rate-Limiting Steps in Yeast Protein Translation
Open accessAbstract
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.
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“Some studies have shown that protein expression level drops if the 5′-end leader region has more secondary structure5,50–53.”
From Algorithm for optimized mRNA design improves stability and immunogenicity (2023) · cites this paper as [52]
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“Most surprising, in contrast to previous reports47–49, we found 5’ UTRs that are highly structured, such as the dengue virus (DEN2), can support efficient translation.”
From Combinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics (2022) · cites this paper as [49]
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BackgroundResultInfluentialAlgorithm for optimized mRNA design improves stability and immunogenicity
Zhang, H., Zhang, L., Lin, A., Xu, C., Li, Z., Liu, K., Liu, B., Ma, X., Zhao, F., Jiang, H., et al. (2023) · Nature · doi:10.1038/s41586-023-06127-z · Cited by 531
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Khajuria, R. K., Munschauer, M., Ulirsch, J. C., Fiorini, C., Ludwig, L. S., McFarland, S. K., Abdulhay, N. J., Specht, H., Keshishian, H., Mani, D. R., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.036 · Cited by 416
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BackgroundInfluentialRibosome Footprint Profiling of Translation throughout the Genome
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BackgroundCombinatorial optimization of mRNA structure, stability, and translation for RNA-based therapeutics
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BackgroundWidespread Co-translational RNA Decay Reveals Ribosome Dynamics
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BackgroundMethodTranslation inhibitors cause abnormalities in ribosome profiling experiments
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Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions
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Liu, Y., Yang, Q., & Zhao, F. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-071320-112701 · Cited by 254
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BackgroundQuantitative profiling of initiating ribosomes in vivo
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InfluentialProtein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates
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“As the high codon adaptation index exhibited by these ORFs would predict fast elongation and thereby low ribosome density (44), high ribosome density on short ORFs has also been interpreted as evidence for initiation being the main determinant of ribosome density.”
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Synonymous Codons: Choose Wisely for Expression
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The ribosome in action: Tuning of translational efficiency and protein folding
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“This lag was similar in length to the observed lifetime of the NSP1–40S subunit interaction (at least ∼250 s) and longer than the time frame of translation initiation on many mRNAs (<60 s) (61, 62), the presumptive rate-limiting phase of protein synthesis (26, 61).”
BackgroundMultiple roles of the coding sequence 5′ end in gene expression regulation
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“The effect becomes apparent when the cellular resources for protein turnover, especially the ribosomes producing other proteins, are overstretched, monopolized by a strong expression of unnecessary proteins (Stoebel et al., 2008; Shachrai et al., 2010; Shah et al., 2013).”
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BackgroundOperon mRNAs are organized into ORF-centric structures that predict translation efficiency
Burkhardt, D. H., Rouskin, S., Zhang, Y., Li, G., Weissman, J. S., & Gross, C. A. (2017) · eLife · doi:10.7554/elife.22037 · Cited by 166
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“A rapidly dividing yeast cell growing on rich medium is estimated to synthesize nearly 13,000 proteins per second (von der Haar 2008), limited by the availability of ribosomes (Shah et al. 2013).”
BackgroundInsights into the mechanisms of eukaryotic translation gained with ribosome profiling
Andreev, D. E., O’Connor, P. B. F., Loughran, G., Dmitriev, S. E., Baranov, P. V., & Shatsky, I. N. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1190 · Cited by 151
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BackgroundExploring the potential of Saccharomyces cerevisiae for biopharmaceutical protein production
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“In addition, protein production in yeast cells might be typically limited by the availability of free ribosomes under specific conditions [31,32].”
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“We observed a similar effect of intraribosomal events when we simulated a model for yeast translation (Shah et al., 2013) (Figure S2A).”
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BackgroundImaging mRNA In Vivo, from Birth to Death
Tutucci, E., Livingston, N. M., Singer, R. H., & Wu, B. (2018) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-070317-033037 · Cited by 138
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Does functional specialization of ribosomes really exist?
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“Because initiation is the limiting step in translation (Lackner et al. 2007; Shah et al. 2013), and involves association of ribosomal subunits with themRNA, first principle considerations suggest that initiation rates (for all mRNAs) should be proportional to ribosome concentrations.”
BackgroundCotranscriptional events in eukaryotic ribosome synthesis
Turowski, T. W., & Tollervey, D. W. (2014) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1263 · Cited by 130
“Despite substantial progress in understanding the cotranscriptional events in ribosome synthesis, many outstanding questions remain: (1) How do the SSU and/or LSU processome complexes communicate with Pol I? (2) What intermediates during ribosome synthesis are subject to surveillance? (3) How is the timing of pre-40S…”
BackgroundThe ribosomal protein Asc1/RACK1 is required for efficient translation of short mRNAs
Thompson, M. K., Rojas-Durán, M. F., Gangaramani, P., & Gilbert, W. V. (2016) · eLife · doi:10.7554/elife.11154 · Cited by 131
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BackgroundInfluentialThe ribosome, (slow) beating heart of cancer (stem) cell
Bastide, A., & David, A. (2018) · Oncogenesis · doi:10.1038/s41389-018-0044-8 · Cited by 125
The Growing Toolbox for Protein Synthesis Studies
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Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation
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Codon Usage and Splicing Jointly Influence mRNA Localization
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“In bacteria and yeast, strong mRNA folding near the start codon prevents ribosome binding and reduces translation efficiency, resulting in selection against strongly folded 50 mRNA regions (Kudla et al., 2009; Shah et al., 2013).”
BackgroundResultSelf-citationComparative survey of the relative impact of mRNA features on local ribosome profiling read density
O’Connor, P. B. F., Andreev, D. E., & Baranov, P. V. (2016) · Nature Communications · doi:10.1038/ncomms12915 · Cited by 109
Gene Architectures that Minimize Cost of Gene Expression
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Duc, K. D., & Song, Y. S. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007166 · Cited by 101
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“Recent studies have argued that the rate-limiting component ねぬは in protein synthesis is ribosome availability and transcripts possessing a short 5’UTR ねぬば essentially out compete longer transcripts with highly structured 5’ UTRs (60).”
BackgroundInfluentialAccurate design of translational output by a neural network model of ribosome distribution
Tunney, R. J., McGlincy, N. J., Graham, M. E., Naddaf, N., Pachter, L. S., & Lareau, L. F. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0080-2 · Cited by 95
tRNA Metabolism and Neurodevelopmental Disorders
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“Of the four different steps, translation initiation is generally the rate-limiting event [13].”
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“These considerable resources are devoted to ribosomes because ribosome abundance is, except under extreme nutrient deprivation, rate limiting for protein synthesis and organismal growth (Shah et al., 2013).”
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“Recent studies in eukaryotes have shown that short genes are transcribed and translated rapidly compared with longer genes, perhaps providing a mechanism for fast response to changes in conditions or during development (Shah et al., 2013; Heyn et al., 2014).”
BackgroundImpacts of uORF codon identity and position on translation regulation
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eIF5B gates the transition from translation initiation to elongation
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Secondary structures in RNA synthesis, splicing and translation
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Metadata
- Authors
- Shah, P., Ding, Y., Niemczyk, M., Kudla, G., & Plotkin, J. B.
- Affiliations
- University of Pennsylvania (US)
- Wellcome Centre for Cell Biology (GB)
- Corresponding author
- Plotkin, Joshua B.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 153
- Issue
- 7
- Pages
- 1589-1601
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3694300
- OpenAlex
- W2011503994
- Cited by
- 463
- References
- 72
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 31 · 2023: 33 · 2022: 37 · 2021: 27 · 2020: 40 · 2019: 37 · 2018: 42 · 2017: 50 · 2016: 48 · 2015: 26 · 2014: 44 · 2013: 9
- FWCI
- 18.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Burroughs Wellcome Fund
- Army Research Office (D12AP00025, W911NF-12-1-0552)
- James S. McDonnell Foundation
- David and Lucile Packard Foundation
- U.S. Department of the Interior
- Wellcome Trust (077248)
- Alfred P. Sloan Foundation (RFP-12-16)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- mRNA translation, ribosome occupancy, translation initiation rate, codon usage bias, free ribosomes, protein production, Saccharomyces cerevisiae, tRNA availability, stress response
- MeSH terms
- Codon, Markov Chains, Models, Genetic, Ribosomes, RNA, Messenger, RNA, Transfer, Saccharomyces cerevisiae, Protein Biosynthesis
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