Widespread Selection for Local RNA Secondary Structure in Coding Regions of Bacterial Genes

Katz, Luba; Burge, Christopher B.

doi:10.1101/gr.1257503

Cited by 180 publications

(218 citation statements)

References 44 publications

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“…We compared the folding profiles with those obtained for randomized versions of the genomes of the analyzed organisms, preserving the original codon bias and amino acid composition (Materials and Methods). In both E. coli and S. cerevisiae, we found that for windows more distant from the beginning of the ORF (starting from window index 18 and 10 in E. coli and S. cerevisiae, respectively; window index denotes the distance in nucleotides from the beginning of the ORF and the beginning of the window; negative window index denotes a window that begins before the beginning of the ORF), these random sequences show higher (significantly higher in most of the windows) folding energy (i.e., weaker folding) than the original profile, thus supporting previous results (17) (Fig. 1).…”

Section: Resultssupporting

confidence: 85%

Translation efficiency is determined by both codon bias and folding energy

Tuller

Waldman²,

Kupiec³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

501

598

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Synonymous mutations do not alter the protein produced yet can have a significant effect on protein levels. The mechanisms by which this effect is achieved are controversial; although some previous studies have suggested that codon bias is the most important determinant of translation efficiency, a recent study suggested that mRNA folding at the beginning of genes is the dominant factor via its effect on translation initiation. Using the Escherichia coli and Saccharomyces cerevisiae transcriptomes, we conducted a genome-scale study aiming at dissecting the determinants of translation efficiency. There is a significant association between codon bias and translation efficiency across all endogenous genes in E. coli and S. cerevisiae but no association between folding energy and translation efficiency, demonstrating the role of codon bias as an important determinant of translation efficiency. However, folding energy does modulate the strength of association between codon bias and translation efficiency, which is maximized at very weak mRNA folding (i.e., high folding energy) levels. We find a strong correlation between the genomic profiles of ribosomal density and genomic profiles of folding energy across mRNA, suggesting that lower folding energies slow down the ribosomes and decrease translation efficiency. Accordingly, we find that selection forces act near uniformly to decrease the folding energy at the beginning of genes. In summary, these findings testify that in endogenous genes, folding energy affects translation efficiency in a global manner that is not related to the expression levels of individual genes, and thus cannot be detected by correlation with their expression levels.mRNA folding | protein abundance | synonymous mutations | ribosome density | translation initiation

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Section: Resultssupporting

confidence: 85%

Translation efficiency is determined by both codon bias and folding energy

Tuller

Waldman²,

Kupiec³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

501

598

View full text Add to dashboard Cite

show abstract

“…These results have been interpreted as indicative of widespread regulation of translation and/or mRNA decay in prokaryotes by mechanisms involving coding-region hairpins (Katz & Burge, 2003).…”

Section: Discussionmentioning

confidence: 89%

The signal peptide sequence of a lytic transglycosylase of Neisseria meningitidis is involved in regulation of gene expression

Serruto

Galeotti

2004

Microbiology

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The 60 nucleotides encoding the signal peptide of the Neisseria meningitidis membrane-bound lytic transglycosylase (MltA) homologue GNA33 were found to exert a negative regulatory effect on expression of GNA33 from either a T7-or a P lac -driven system in Escherichia coli. Down-regulation was observed to occur at the transcriptional/post-transcriptional level and could possibly be ascribed to the formation of a stem-loop secondary structure within the signal peptide sequence. Slowing down the transcription rate through inhibition/titration of the RNA polymerase resulted in a considerable increase in mRNA accumulation, suggesting that a better coupling of translation to transcription would impede the formation of the putative secondary structure. Screening of synonymous mutations in the signal peptide sequence that showed high-level expression of an in-frame fusion to a reporter resulted in the isolation of several deletion mutants lacking most of the sequence participating in the putative secondary structure. Interestingly, the increase in the steady-state mRNA level observed in deletion mutants was higher, reaching a 300-fold increment, than that found in substitution mutants. Our results support the hypothesis that the rate of transcription controls the formation of a secondary structure in the region of the GNA33 transcript corresponding to the signal peptide sequence and this, when formed, negatively regulates expression.

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“…WC base pair formation lowers the average free energy, dG, of the RNA and the magnitude of change is proportional to the number of base pair formations. Therefore the free folding energy (FFE) is used to characterize the local complementarity of nucleic acids [13]. The free folding energy is defined as FFE=(dG shuffled -dG native )/L×100, where L is the length of the nucleic acid, i.e., free energy difference between native and shuffle (randomized) nucleic acids per 100 nucleotides.…”

Section: Methodsmentioning

confidence: 99%

The Meaning of a Redundant Codon: There is Protein Folding Information in Nucleic Acids in Addition to the Genetic Code

Biro¹,

Biro²

2006

American J. of Biochemistry and Biotechnology

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All the information necessary for protein folding is supposed to be present in the amino acid sequence. It is still not possible to provide specific ab initio structure predictions by bioinformatical methods. It is suspected that additional folding information is present in protein coding nucleic acid sequences, which is not represented by the known genetic code. Nucleic acid subsequences comprising the 1st and/or 3rd codon residues in mRNAs express significantly higher free folding energy (FFE) than the subsequence containing only the 2nd residues (p<0.0001, n=81). This periodic FFE difference is not present in introns and therefore it is a specific physico-chemical characteristic of coding sequences and it might contribute to unambiguous definition of codon boundaries during translation. The FFE in the 1st and 3rd residues is additive, which suggests that these residues contain a significant number of complementary bases and contribute to selection for local RNA secondary structures in coding regions. This periodic, codon-related structure-forming of mRNAs indicates a connection between the structure of exons and the corresponding (translated) proteins. The folding energy dot plots of RNAs and the residue contact maps of the coded proteins are indeed similar. Residue contact statistics using 81 different protein structures confirmed that amino acids that are coded by partially reverse and complementary codons (Watson-Crick (WC) base pairs at the 1st and 3rd codon positions and translated in reverse orientation) are preferentially co-located in protein structures. Exons are distinguished from introns and codon boundaries are physico-chemically defined by periodically distributed FFE differences between codon positions. There is a selection for local RNA secondary structures in coding regions and this nucleic acid structure resembles the folding profiles of the coded proteins. The preferentially (specifically) interacting amino acids are coded by partially complementary codons, which strongly supports the connection between mRNA and the corresponding protein structures and indicates that there is protein folding information in nucleic acids that is not present in the genetic code. This might give some additional explanation of codon redundancy.

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Widespread Selection for Local RNA Secondary Structure in Coding Regions of Bacterial Genes

Cited by 180 publications

References 44 publications

Translation efficiency is determined by both codon bias and folding energy

Translation efficiency is determined by both codon bias and folding energy

The signal peptide sequence of a lytic transglycosylase of Neisseria meningitidis is involved in regulation of gene expression

The Meaning of a Redundant Codon: There is Protein Folding Information in Nucleic Acids in Addition to the Genetic Code

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