A Single Synonymous Variant (c.354G&gt;A [p.P118P]) in ADAMTS13 Confers Enhanced Specific Activity

Hunt, Ryan; Hettiarachchi, Gaya; Katneni, Upendra; Hernandez, Nancy; Holcomb, David D.; Kames, Jacob; Alnifaidy, Redab; Lin, Brian C.; Hamasaki-Katagiri, Nobuko; Wesley, Aaron; Kafri, Tal; Morris, Christina; Bouché, Laura; Panico, Maria; Schiller, Tal; Ibla, Juan C.; Bar, Haim; Ismail, Amra; Morris, Howard R.; Komar, Anton A.

doi:10.3390/ijms20225734

Cited by 24 publications

(21 citation statements)

References 65 publications

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“…Codon usage in KRAS, which encodes an oncogenic Ras GTPase family member, was shown to regulate the expression and protein structure of KRAS protein when expressed in human cells [22,23]. More recently, codon usage optimization of the coagulation factor IX and a single SNP of the ADAMTS13 has been shown to affect protein folding or activity [82,83]. Together, these studies firmly established the universal role of codon usage in protein folding in both prokaryotes and eukaryotes.…”

Section: The Role Of Codon Usage In Protein Foldingmentioning

confidence: 89%

A code within the genetic code: codon usage regulates co-translational protein folding

2020

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The genetic code is degenerate, and most amino acids are encoded by two to six synonymous codons. Codon usage bias, the preference for certain synonymous codons, is a universal feature of all genomes examined. Synonymous codon mutations were previously thought to be silent; however, a growing body evidence now shows that codon usage regulates protein structure and gene expression through effects on co-translational protein folding, translation efficiency and accuracy, mRNA stability, and transcription. Codon usage regulates the speed of translation elongation, resulting in non-uniform ribosome decoding rates on mRNAs during translation that is adapted to co-translational protein folding process. Biochemical and genetic evidence demonstrate that codon usage plays an important role in regulating protein folding and function in both prokaryotic and eukaryotic organisms. Certain protein structural types are more sensitive than others to the effects of codon usage on protein folding, and predicted intrinsically disordered domains are more prone to misfolding caused by codon usage changes than other domain types. Bioinformatic analyses revealed that gene codon usage correlates with different protein structures in diverse organisms, indicating the existence of a codon usage code for co-translational protein folding. This review focuses on recent literature on the role and mechanism of codon usage in regulating translation kinetics and co-translational protein folding.

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Section: The Role Of Codon Usage In Protein Foldingmentioning

confidence: 89%

A code within the genetic code: codon usage regulates co-translational protein folding

2020

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“…It became clear that synonymous codon changes could also cause the development of human disease [149][150][151][152][153][154] and potentially affect safety and efficacy of the recombinant/therapeutic proteins [155][156][157]. Surprisingly, it was also found that even a single synonymous mutation can be deleterious to protein folding and function [141,152,158].…”

Section: Codon Usage Code For Protein Folding In the Cell: Importancementioning

confidence: 99%

A Code Within a Code: How Codons Fine-Tune Protein Folding in the Cell

Komar

2021

Biochemistry Moscow

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The genetic code sets the correspondence between the sequence of a given nucleotide triplet in an mRNA molecule, called a codon, and the amino acid that is added to the growing polypeptide chain during protein synthesis. With four bases (A, G, U, and C), there are 64 possible triplet codons: 61 sense codons (encoding amino acids) and 3 nonsense codons (so-called, stop codons that define termination of translation). In most organisms, there are 20 common/standard amino acids used in protein synthesis; thus, the genetic code is redundant with most amino acids (with the exception of Met and Trp) are being encoded by more than one (synonymous) codon. Synonymous codons were initially presumed to have entirely equivalent functions, however, the finding that synonymous codons are not present at equal frequencies in mRNA suggested that the specific codon choice might have functional implications beyond coding for amino acid. Observation of nonequivalent use of codons in mRNAs implied a possibility of the existence of auxiliary information in the genetic code. Indeed, it has been found that genetic code contains several layers of such additional information and that synonymous codons are strategically placed within mRNAs to ensure a particular translation kinetics facilitating and fine-tuning co translational protein folding in the cell via step-wise/sequential structuring of distinct regions of the polypeptide chain emerging from the ribosome at different points in time. This review summarizes key findings in the field that have identified the role of synonymous codons and their usage in protein folding in the cell.

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“…In eukaryotes, a synonymous single-nucleotide polymorphism of the human MDR1 gene was previously shown to cause altered protein activity of the MDR1 protein transiently overexpressed in human cells, suggesting the involvement of codon usage in eukaryotic protein folding ( 39 ). More recently, codon usage was also shown to influence protein activity and/or structures of several other human proteins ( 28 , 45 , 48 – 50 ). However, those previous studies relied on protein overexpression, which could also influence protein folding in cells, and the degree of impact of codon usage on protein structure/function was often modest.…”

Section: Introductionmentioning

confidence: 99%

Nonoptimal Codon Usage Is Critical for Protein Structure and Function of the Master General Amino Acid Control Regulator CPC-1

Lyu

Liu

2020

mBio

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Under amino acid starvation conditions, eukaryotic organisms activate a general amino acid control response. In Neurospora crassa, Cross Pathway Control Protein 1 (CPC-1), the ortholog of the Saccharomyces cerevisiae bZIP transcription factor GCN4, functions as the master regulator of the general amino acid control response. Codon usage biases are a universal feature of eukaryotic genomes and are critical for regulation of gene expression. Although codon usage has also been implicated in the regulation of protein structure and function, genetic evidence supporting this conclusion is very limited. Here, we show that Neurospora cpc-1 has a nonoptimal NNU-rich codon usage profile that contrasts with the strong NNC codon preference in the genome. Although substitution of the cpc-1 NNU codons with synonymous NNC codons elevated CPC-1 expression in Neurospora, it altered the CPC-1 degradation rate and abolished its amino acid starvation-induced protein stabilization. The codon-manipulated CPC-1 protein also exhibited different sensitivity to limited protease digestion. Furthermore, CPC-1 functions in rescuing the cell growth of the cpc-1 deletion mutant and activation of the expression of its target genes were impaired by the synonymous codon changes. Together, these results reveal the critical role of codon usage in regulation of CPC-1 expression and function and establish a genetic example of the importance of codon usage in protein folding. IMPORTANCE The general amino acid control response is critical for adaptation of organisms to amino acid starvation conditions. The preference to use certain synonymous codons is a universal feature of all genomes. Synonymous codon changes were previously thought to be silent mutations. In this study, we showed that the Neurospora cpc-1 gene has an unusual codon usage profile compared to other genes in the genome. We found that codon optimization of the cpc-1 gene without changing its amino acid sequence resulted in elevated CPC-1 expression, an altered protein degradation rate, and impaired protein functions due to changes in protein structure. Together, these results reveal the critical role of synonymous codon usage in regulation of CPC-1 expression and function and establish a genetic example of the importance of codon usage in protein structure.

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A Single Synonymous Variant (c.354G>A [p.P118P]) in ADAMTS13 Confers Enhanced Specific Activity

Cited by 24 publications

References 65 publications

A code within the genetic code: codon usage regulates co-translational protein folding

A code within the genetic code: codon usage regulates co-translational protein folding

A Code Within a Code: How Codons Fine-Tune Protein Folding in the Cell

Nonoptimal Codon Usage Is Critical for Protein Structure and Function of the Master General Amino Acid Control Regulator CPC-1

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