How Messenger RNA and Nascent Chain Sequences Regulate Translation Elongation

Choi, Junhong; Grosely, Rosslyn; Prabhakar, Arjun; Lapointe, Christopher P.; Wang, Jinfan; Puglisi, Joseph D.

doi:10.1146/annurev-biochem-060815-014818

Cited by 70 publications

(60 citation statements)

References 184 publications

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“…Translation rate is generally determined by translation initiation rate 1 . Translation efficiency (TE), that is the relative number of protein molecules synthesized per equally transcribed mRNAs, is mainly governed by translation initiation, that in turn depends primarily on the sequence of mRNA 5' UTR 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Other studies claim that translation elongation rates can only enhance protein expression to a small extent, and that, even though it is located inside the open reading frame, the low-efficiency ramp affects translation initiation rates primarily 12,13 . Despite the many examples of connections between the role of translation elongation and protein expression levels, there is currently no clear understanding of the mechanisms by which translation elongation exerts translational control 1,14,15 .…”

Section: Introductionmentioning

confidence: 99%

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From reporters to endogenous genes: the impact of the first five codons on translation efficiency in Escherichia coli

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Translation initiation is a critical step in the regulation of protein synthesis, and it is subjected to different control mechanisms, such as 5' UTR secondary structure and initiation codon context, that can influence the rates at which initiation and consequentially translation occurs. For some genes, translation elongation also affects the protein synthesis rate. Recently, it was proposed that the identity of codons three to five, called short translational ramp, have a strong influence on translation elongation and protein expression. By the use of a GFP library where nearly all combinations of nucleotides at these positions were created, it was demonstrated that some of nucleotides combinations increased GFP expression up to four orders of magnitude by enhancing their translation efficiency (TE). While it is clear that the short ramp can influence protein expression levels of artificial constructs, its impact on physiological proteins is still unknown. In this work, we aimed to investigate the relevance of the short translational ramp on a physiological context. Through bioinformatics analysis, we identified the nucleotide combinations from the GFP library on Escherichia coli genes and examined their correlation with TE. We observed that E. coli genes were enriched with nucleotide compositions that enhanced protein expression on the GFP library, but, surprisingly, it seems to affect the TE only marginally.Nevertheless, our data indicate that different enterobacteria present similar nucleotide composition enrichment as E. coli, suggesting an evolutionary pressure towards the conservation of the short translational ramp.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

From reporters to endogenous genes: the impact of the first five codons on translation efficiency in Escherichia coli

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et al. 2019

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“…The results above suggest the Shuf1 synonymous codon substitutions impair CAT cotranslational folding by altering local patterns of translation elongation. In vitro, synonymous codons have been shown to alter elongation rate either by altering the rate of decoding (59) or by altering downstream mRNA stability, which can impede ribosome translocation (60). In vivo, there is some evidence that stable mRNA stem-loop structures can alter the elongation rate of the ribosome (61-63), although other studies have detected no difference (38,64,65), likely due to destabilization of mRNA structure by polysomes and/or the helicase activity of the ribosome.…”

Section: Mrna Secondary Structural Stability Does Not Explain Shuf1 Gmentioning

confidence: 99%

Synonymous codon substitutions perturb co-translational protein foldingin vivoand impair cell fitness

Walsh

Bowman

Clark

2019

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AbstractIn the cell, proteins are synthesized from N- to C-terminus and begin to fold during translation. Co-translational folding mechanisms are therefore linked to elongation rate, which varies as a function of synonymous codon usage. However, synonymous codon substitutions can affect many distinct cellular processes, which has complicated attempts to deconvolve the extent to which synonymous codon usage can promote or frustrate proper protein folding in vivo. Although previous studies have shown that some synonymous changes can lead to different final structures, other substitutions will likely be more subtle, perturbing predominantly the protein folding pathway without radically altering the final structure. Here we show that synonymous codon substitutions encoding a single essential enzyme lead to dramatically slower cell growth. These mutations do not prevent active enzyme formation; instead, they predominantly alter the protein folding mechanism, leading to enhanced degradation in vivo. These results support a model where synonymous codon substitutions can impair cell fitness by significantly perturbing co-translational protein folding mechanisms, despite the chaperoning provided by the cellular protein homeostasis network.SignificanceMany proteins that are incapable of refolding in vitro nevertheless fold efficiently to their native state in the cell. This suggests that more information than the amino acid sequence is required to properly fold these proteins. Here we show that synonymous mRNA mutations can alter a protein folding mechanism in vivo, leading to changes in cellular fitness. This work demonstrates that synonymous codon selection can play an important role in supporting efficient protein production in vivo.

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“…The geometric and structural variation of the exit tunnel may have several functional and biophysical implications, as the nascent chain transit can be affected. On the one hand, a too narrow tunnel could obstruct the elongation of the nascent chain and generate tunnel-peptide interactions that might alter the elongation rate during protein synthesis [4,41,42]. On the other hand, a too large tunnel radius could lead to an increase of conformational sampling [43,44,45] and hence misfolding events.…”

Section: Impact On the Nascent Polypeptide Chain Transitmentioning

confidence: 99%

“…These processes rely on the structural properties of the ribosome, through interactions with different elements such as binding factors, tRNAs, or the nascent polypeptide chain. For example, it has been shown that some specific sequence motifs associated with antibiotic treatment could stall the ribosome and subsequently arrest translation [4,5,6,7]. This phenomenon is caused by interactions between the ribosome and the nascent polypeptide chain itself: prior to leaving the ribosome, nascent polypeptides first pass through a structure called the ribosome exit tunnel, spanning from the peptidyl-transferase center (PTC) to the surface of the ribosome.…”

Section: Introductionmentioning

confidence: 99%

Differences in the path to exit the ribosome across the three domains of life

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Batra

Bhattacharya

et al. 2018

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Recent advances in biological imaging have led to a surge of fine-resolution structures of the ribosome from diverse organisms. Comparing these structures, especially the exit tunnel, to characterize the key similarities and differences across species is essential for various important applications, such as designing antibiotic drugs and understanding the intricate details of translation dynamics. Here, we compile and compare 20 fine-resolution cryo-EM and X-ray crystallography structures of the ribosome recently obtained from all three domains of life (bacteria, archaea and eukarya). We first show that a hierarchical clustering of tunnel shapes closely reflects the species phylogeny. Then, by analyzing the ribosomal RNAs and proteins localized near the tunnel, we explain the observed geometric variations and show direct association between the conservations of the geometry, structure, and sequence. We find that the tunnel is more conserved in its upper part, from the polypeptide transferase center to the constriction site. In the lower part, tunnels are significantly narrower in eukaryotes than in bacteria, and we provide evidence for the existence of a second constriction site in eukaryotic tunnels. We also show that ribosomal RNA and protein sequences are more likely to be conserved closer to the tunnel, as is the presence of positively charged amino acids. Overall, our comparative analysis shows how the geometric and biophysical properties of the exit tunnel play an important role in ensuring proper transit of the nascent polypeptide chain, and may explain the differences observed in several co-translational processes across species.

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How Messenger RNA and Nascent Chain Sequences Regulate Translation Elongation

Cited by 70 publications

References 184 publications

From reporters to endogenous genes: the impact of the first five codons on translation efficiency in Escherichia coli

From reporters to endogenous genes: the impact of the first five codons on translation efficiency in Escherichia coli

Synonymous codon substitutions perturb co-translational protein foldingin vivoand impair cell fitness

Differences in the path to exit the ribosome across the three domains of life

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