Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

O’Brien, Edward P.; Vendruscolo, Michele

doi:10.1038/ncomms3988

Cited by 83 publications

(99 citation statements)

References 66 publications

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“…Should the co-translational folding of all proteins be able to be significantly affected by just a few synonymous codons? Recent theoretical papers 3,10,26 demonstrate that the complex interplay of timescales of folding and translation-elongation influences whether a protein's co-translational folding curve is robust or sensitive to changes in codon translation rates. Furthermore, if a domain can populate off-pathway intermediates, synonymous codons can have an even greater impact 3 .…”

Section: Discussionmentioning

confidence: 99%

“…This limitation can be overcome by using previouslyreported mathematical expressions for the P F,B (i) (ref. 26) and P F,R (t, t 0 ) (ref. 37) terms in equation (1) that describe cotranslational folding mechanisms involving three states.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, it has been demonstrated that the tertiary folding of protein domains can begin during their synthesis by the ribosome 7,15,19,31 . Translation introduces an additional process that can influence nascent protein folding; hence, the kinetic equations describing protein folding have recently been expanded to account for the impact of codon translation rates 10,26 . These new models, while successfully tested against results from molecular dynamics simulations 10 , have not previously been validated against experimental data.…”

Section: Discussionmentioning

confidence: 99%

“…The efficiency of co-translational folding can be influenced by the variability in translation rates from one codon position to the next along an mRNA molecule [26][27][28] . Our previous predictions (Fig.…”

Section: A5mentioning

confidence: 99%

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Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

Nissley

2017

Biophysical Journal

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The rates at which domains fold and codons are translated are important factors in determining whether a nascent protein will co-translationally fold and function or misfold and malfunction. Here we develop a chemical kinetic model that calculates a protein domain's co-translational folding curve during synthesis using only the domain's bulk folding and unfolding rates and codon translation rates. We show that this model accurately predicts the course of co-translational folding measured in vivo for four different protein molecules. We then make predictions for a number of different proteins in yeast and find that synonymous codon substitutions, which change translation-elongation rates, can switch some protein domains from folding post-translationally to folding co-translationally-a result consistent with previous experimental studies. Our approach explains essential features of co-translational folding curves and predicts how varying the translation rate at different codon positions along a transcript's coding sequence affects this self-assembly process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: A5mentioning

confidence: 99%

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Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

Nissley

2017

Biophysical Journal

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“…We anticipate that an optimal translation protocol [48] could be predicted with knowledge of the substructure-specific folding and translation rates, as well as their propensities for forming non-native interactions, including interactions with the surface of the ribosome [49]. In addition, an optimal translation protocol is likely to be affected by the presence of misfolded intermediates, which may be avoided by increasing the local translation rate [50,51].The approach that we have taken in this work improves upon earlier studies of rare-codon usage, which have addressed alternative hypotheses regarding translational pausing but yielded mixed results [35,38,[52][53][54][55][56]. In addition to our distinct focus on co-translational folding pathways, our conclusions are more robust due to our use of a multiple-sequence analysis to detect evolutionary conservation, as well as our formulation of a neutral model that controls for both amino-acid composition and the inherent codon-usage variability across genes.…”

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confidence: 99%

Evidence of evolutionary selection for co-translational folding

Jacobs

Shakhnovich

2017

Preprint

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Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from co-translational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for co-translational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with co-translational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of co-translational folding account for the majority of these loci across more than 500 E. coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context. INTRODUCTIONMany proteins can begin folding to their native states before their synthesis is complete [1,2]. As much as one-third of a bacterial proteome is believed to fold cotranslationally [3], with an even higher percentage likely in more slowly translated eukaryotic proteomes. Numerous experiments on both natural and engineered aminoacid sequences have shown that folding during synthesis can have profound effects: compared to denatured and refolded chains, co-translationally folded proteins may be less prone to misfolding [4][5][6][7][8][9][10][11], aggregation [12] and degradation [13], or they may preferentially adopt alternate stable structures [14][15][16]. Because the timescales for protein synthesis and folding are often similar [17,18], it is clear that the rate of translation can be used to tune the self-assembly of peptide chains in vivo [19,20]. To this point, however, there exists little evidence that evolution has selected specifically for efficient co-translational folding kinetics across any substantial fraction of an organism's proteome.In this work, we provide evidence that evolutionary selection has tuned protein-translation rates to optimize co-translational folding pathways. Our approach is motivated by the hypothesis that pauses during protein synthesis may be beneficial for promoting the formation of native structure. By increasing the separation between the timescales for folding and translation, such pauses may promote the assembly of on-pathway intermediates, which, in turn, template the growth of further native structure. Many experimental and computational studies have shown that protein-folding naturally proceeds in a step-wise manner via structurally distinct intermediates [21,22], and that...

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The ribosome in action: Tuning of translational efficiency and protein folding

2016

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The cellular proteome is shaped by the combined activities of the gene expression and quality control machineries. While transcription plays an undoubtedly important role, in recent years also translation emerged as a key step that defines the composition and quality of the proteome and the functional activity of proteins in the cell. Among the different post-transcriptional control mechanisms, translation initiation and elongation provide multiple checkpoints that can affect translational efficiency. A multitude of specific signals in mRNAs can determine the frequency of translation initiation, choice of the open reading frame, global and local elongation velocities, and the folding of the emerging protein. In addition to specific signatures in the mRNAs, also variations in the global pools of translation components, including ribosomes, tRNAs, mRNAs, and translation factors can alter translational efficiencies. The cellular outcomes of phenomena such as mRNA codon bias are sometimes difficult to understand due to the staggering complexity of covariates that affect codon usage, translation, and protein folding. Here we summarize the experimental evidence on how the ribosome-together with the other components of the translational machinery-can alter translational efficiencies of mRNA at the initiation and elongation stages and how translation velocity affects protein folding. We seek to explain these findings in the context of mechanistic work on the ribosome. The results argue in favour of a new understanding of translation control as a hub that links mRNA homeostasis to production and quality control of proteins in the cell.

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Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates

Cited by 83 publications

References 66 publications

Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

Accurate Prediction of Cellular Co-Translational Folding Indicates Proteins can Switch from Post- to Co-Translational Folding

Evidence of evolutionary selection for co-translational folding

The ribosome in action: Tuning of translational efficiency and protein folding

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