scholarly journals %MinMax: A versatile tool for calculating and comparing synonymous codon usage and its impact on protein folding

2017 ◽  
Vol 27 (1) ◽  
pp. 356-362 ◽  
Author(s):  
Anabel Rodriguez ◽  
Gabriel Wright ◽  
Scott Emrich ◽  
Patricia L. Clark
Keyword(s):  
Protein Folding ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Synonymous Codon Usage ◽  
Versatile Tool

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

2019 ◽  
Author(s):  
Ian M. Walsh ◽  
Micayla A. Bowman ◽  
Iker F. Soto ◽  
Anabel Rodriguez ◽  
Patricia L. Clark
Keyword(s):  
Protein Folding ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Cellular Protein ◽  
Synonymous Codon Usage ◽  
Folding Mechanism ◽  
C Terminus ◽  
Essential Enzyme

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 foldingin 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 degradationin 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 refoldingin vitronevertheless 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 mechanismin vivo, leading to changes in cellular fitness. This work demonstrates that synonymous codon selection can play an important role in supporting efficient protein productionin vivo.

scholarly journals Synonymous codon substitutions perturb cotranslational protein folding in vivo and impair cell fitness

2020 ◽  
Vol 117 (7) ◽  
pp. 3528-3534 ◽  
Author(s):  
Ian M. Walsh ◽  
Micayla A. Bowman ◽  
Iker F. Soto Santarriaga ◽  
Anabel Rodriguez ◽  
Patricia L. Clark
Keyword(s):  
Protein Folding ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Cellular Protein ◽  
Synonymous Codon Usage ◽  
Cellular Processes ◽  
C Terminus ◽  
Enzyme Formation ◽  
Essential Enzyme

In the cell, proteins are synthesized from N to C terminus and begin to fold during translation. Cotranslational 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 in which synonymous codon substitutions can impair cell fitness by significantly perturbing cotranslational protein folding mechanisms, despite the chaperoning provided by the cellular protein homeostasis network.

scholarly journals Network analysis of synonymous codon usage

2020 ◽  
Vol 36 (19) ◽  
pp. 4876-4884
Author(s):  
Khalique Newaz ◽  
Gabriel Wright ◽  
Jacob Piland ◽  
Jun Li ◽  
Patricia L Clark ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Folding ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Protein Structures ◽  
Synonymous Codon Usage ◽  
Supplementary Information ◽  
Rare Codons ◽  
Model Protein ◽  
Structural Positions

Abstract Motivation Most amino acids are encoded by multiple synonymous codons, some of which are used more rarely than others. Analyses of positions of such rare codons in protein sequences revealed that rare codons can impact co-translational protein folding and that positions of some rare codons are evolutionarily conserved. Analyses of their positions in protein 3-dimensional structures, which are richer in biochemical information than sequences alone, might further explain the role of rare codons in protein folding. Results We model protein structures as networks and use network centrality to measure the structural position of an amino acid. We first validate that amino acids buried within the structural core are network-central, and those on the surface are not. Then, we study potential differences between network centralities and thus structural positions of amino acids encoded by conserved rare, non-conserved rare and commonly used codons. We find that in 84% of proteins, the three codon categories occupy significantly different structural positions. We examine protein groups showing different codon centrality trends, i.e. different relationships between structural positions of the three codon categories. We see several cases of all proteins from our data with some structural or functional property being in the same group. Also, we see a case of all proteins in some group having the same property. Our work shows that codon usage is linked to the final protein structure and thus possibly to co-translational protein folding. Availability and implementation https://nd.edu/∼cone/CodonUsage/. Supplementary information Supplementary data are available at Bioinformatics online.

Codon Usage Bias Covaries With Expression Breadth and the Rate of Synonymous Evolution in Humans, but This Is Not Evidence for Selection

Genetics ◽  
2001 ◽  
Vol 159 (3) ◽  
pp. 1191-1199
Author(s):  
Araxi O Urrutia ◽  
Laurence D Hurst
Keyword(s):  
Codon Usage ◽  
Codon Bias ◽  
Synonymous Codon ◽  
Nucleotide Composition ◽  
Synonymous Codon Usage ◽  
Synonymous Substitutions ◽  
Numerous Species ◽  
Nucleotide Content ◽  
Expression Breadth ◽  
Human Genes

Abstract In numerous species, from bacteria to Drosophila, evidence suggests that selection acts even on synonymous codon usage: codon bias is greater in more abundantly expressed genes, the rate of synonymous evolution is lower in genes with greater codon bias, and there is consistency between genes in the same species in which codons are preferred. In contrast, in mammals, while nonequal use of alternative codons is observed, the bias is attributed to the background variance in nucleotide concentrations, reflected in the similar nucleotide composition of flanking noncoding and exonic third sites. However, a systematic examination of the covariants of codon usage controlling for background nucleotide content has yet to be performed. Here we present a new method to measure codon bias that corrects for background nucleotide content and apply this to 2396 human genes. Nearly all (99%) exhibit a higher amount of codon bias than expected by chance. The patterns associated with selectively driven codon bias are weakly recovered: Broadly expressed genes have a higher level of bias than do tissue-specific genes, the bias is higher for genes with lower rates of synonymous substitutions, and certain codons are repeatedly preferred. However, while these patterns are suggestive, the first two patterns appear to be methodological artifacts. The last pattern reflects in part biases in usage of nucleotide pairs. We conclude that we find no evidence for selection on codon usage in humans.

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