Accurate prediction of cellular co-translational folding indicates proteins can switch from post- to co-translational folding

Nissley, Daniel A.; Sharma, Ajeet K.; Ahmed, Nabeel; Friedrich, Ulrike; Krämer, Günter; Bukau, Bernd; O’Brien, Edward P.

doi:10.1038/ncomms10341

Cited by 47 publications

(63 citation statements)

References 66 publications

(105 reference statements)

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“…This is important because translation rates can affect translational fidelity 65 and the conformational state of a nascent peptide in the ribosome 6, 17, 18, 24, 66–68 . Altered rates of translation may also switch the biogenic sequence of folding 69, 70 and alter the final structure and function of a protein 16, 23, 71–73 . Clearly, each of these sequelae have evolved to optimize biogenesis and to avoid the potentially grievous consequences of misfolding.…”

Section: Discussionmentioning

confidence: 99%

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

Delaney

Gamper

et al. 2017

Journal of Molecular Biology

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All proteins are synthesized by the ribosome, a macromolecular complex that accomplishes the life-sustaining tasks of faithfully decoding mRNA and catalyzing peptide bond formation at the peptidyl transferase center (PTC). The ribosome has evolved an exit tunnel to host the elongating new peptide, protect it from proteolytic digestion, and guide its emergence. It is here that the nascent chain begins to fold. This folding process depends on the rate of translation at the PTC. We report here that, besides PTC events, translation kinetics depend on steric constraints on nascent peptide side chains, and that confined movements of cramped side chains within and through the tunnel fine-tune elongation rates.

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Section: Discussionmentioning

confidence: 99%

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

Delaney

Gamper

et al. 2017

Journal of Molecular Biology

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“…162,163 Synonymous mutations that change elongation rates can even switch folding of some protein domains from post-translational to cotranslational. 164 Alterations in codon context caused by synonymous mutations may also induce the mis-incorporation of amino acids, leading to protein misfolding. 165 The analysis in vivo and in vitro of the structure and folding of gamma-B crystallin showed that synonymous mutations can change the fraction of soluble protein in the cell, the sensitivity of the protein to protease digestion, and alter the conformational ensemble of the mature protein 156 (Fig.…”

Section: Elongation Processivity and Protein Foldingmentioning

confidence: 99%

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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“…(4)) to in vivo ribosome profiling data published in Refs. [16] and [44] with NCBI accession numbers GSM1289257 and GSM1949551, respectively. The RNA-Seq data we used for Ref.…”

Section: Calculation Of the Folding Energy Near The 5' Mrna Cap And Ementioning

confidence: 99%

A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data

Sharma

Sormanni²,

Ahmed

et al. 2018

Preprint

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Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions; hence, bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. Applying our methods to data from S. cerevisiae and mouse embryonic stem cells we find that the extracted rates reproduce expected correlations with various molecular properties. A codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated. We also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, is similar to what has been previous reported using another analysis method. This large variability in translation rates suggests that translational regulation might be used by cells to a greater degree than previously thought. ‡ These authors contributed equally to this work.Introduction. Translation-associated rates influence in vivo protein abundance, structure and function. It is therefore crucial to be able to accurately measure these rates. The synthesis of a protein consists of three sequential phasesinitiation, elongation, and termination [1][2][3]. During the initiation phase ribosome subunits form a stable translation-initiation complex at the start codon of the mRNA transcript [4,5]. The ribosome then stochastically moves forward along the transcript one codon at a time during the elongation phase, adding one residue to the nascent chain at each step. The elongation phase is terminated when the ribosome's A-site reaches the stop codon, resulting in release of the fully synthesized protein. The initiation and elongation phases of translation contribute to protein levels inside a cell; indeed, alteration of their rates can cause protein abundance to vary by up to five orders of magnitude [6][7][8], and alter protein structure and function [9]. Termination does not influence the cellular concentration of proteins as it is not a rate limiting step [10]. Therefore, knowledge of translation initiation and codon translation rates are important to understand the regulation of gene expression.Significant efforts have been made to extract these rates from data generated from ribosome profiling experiments [11][12][13][14], a technique that measures the relative ribosome density across transcripts [15]. In a number of methods, the actual rates are not measured but instead a ratio of rates, or other releva...

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Accurate prediction of cellular co-translational folding indicates proteins can switch from post- to co-translational folding

Cited by 47 publications

References 66 publications

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel

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

A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data

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