Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies
Abstract
Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies.
- Authors:
-
[1];
[3];
[1];
[1];
more »
- U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research
- Cleveland State Univ., Cleveland, OH (United States). Center for Gene Regulation in Health and Disease
- Univ. of North Carolina, Chapel Hill, NC (United States)
- Bioverativ, Cambridge, MA (United States)
- SomaLogic, Inc, Boulder, CO (United States)
- National Inst. of Health (NIH), Bethesda, MD (United States). National Center of Biotechnology Information
- Univ. of Connecticut, Storrs, CT (United States). Dept. of Statistics
- Cleveland State Univ., Cleveland, OH (United States). Center for Gene Regulation in health and Disease
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1624503
- Grant/Contract Number:
- SC0014664
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Scientific Reports
- Additional Journal Information:
- Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 2045-2322
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Science & Technology - Other Topics
Citation Formats
Alexaki, Aikaterini, Hettiarachchi, Gaya K., Athey, John C., Katneni, Upendra K., Simhadri, Vijaya, Hamasaki-Katagiri, Nobuko, Nanavaty, Puja, Lin, Brian, Takeda, Kazuyo, Freedberg, Darón, Monroe, Dougald, McGill, Joseph R., Peters, Robert, Kames, Jacob M., Holcomb, David D., Hunt, Ryan C., Sauna, Zuben E., Gelinas, Amy, Janjic, Nebojsa, DiCuccio, Michael, Bar, Haim, Komar, Anton A., and Kimchi-Sarfaty, Chava. Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies. United States: N. p., 2019.
Web. doi:10.1038/s41598-019-51984-2.
Alexaki, Aikaterini, Hettiarachchi, Gaya K., Athey, John C., Katneni, Upendra K., Simhadri, Vijaya, Hamasaki-Katagiri, Nobuko, Nanavaty, Puja, Lin, Brian, Takeda, Kazuyo, Freedberg, Darón, Monroe, Dougald, McGill, Joseph R., Peters, Robert, Kames, Jacob M., Holcomb, David D., Hunt, Ryan C., Sauna, Zuben E., Gelinas, Amy, Janjic, Nebojsa, DiCuccio, Michael, Bar, Haim, Komar, Anton A., & Kimchi-Sarfaty, Chava. Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies. United States. https://doi.org/10.1038/s41598-019-51984-2
Alexaki, Aikaterini, Hettiarachchi, Gaya K., Athey, John C., Katneni, Upendra K., Simhadri, Vijaya, Hamasaki-Katagiri, Nobuko, Nanavaty, Puja, Lin, Brian, Takeda, Kazuyo, Freedberg, Darón, Monroe, Dougald, McGill, Joseph R., Peters, Robert, Kames, Jacob M., Holcomb, David D., Hunt, Ryan C., Sauna, Zuben E., Gelinas, Amy, Janjic, Nebojsa, DiCuccio, Michael, Bar, Haim, Komar, Anton A., and Kimchi-Sarfaty, Chava. Tue .
"Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies". United States. https://doi.org/10.1038/s41598-019-51984-2. https://www.osti.gov/servlets/purl/1624503.
@article{osti_1624503,
title = {Effects of codon optimization on coagulation factor IX translation and structure: Implications for protein and gene therapies},
author = {Alexaki, Aikaterini and Hettiarachchi, Gaya K. and Athey, John C. and Katneni, Upendra K. and Simhadri, Vijaya and Hamasaki-Katagiri, Nobuko and Nanavaty, Puja and Lin, Brian and Takeda, Kazuyo and Freedberg, Darón and Monroe, Dougald and McGill, Joseph R. and Peters, Robert and Kames, Jacob M. and Holcomb, David D. and Hunt, Ryan C. and Sauna, Zuben E. and Gelinas, Amy and Janjic, Nebojsa and DiCuccio, Michael and Bar, Haim and Komar, Anton A. and Kimchi-Sarfaty, Chava},
abstractNote = {Synonymous codons occur with different frequencies in different organisms, a phenomenon termed codon usage bias. Codon optimization, a common term for a variety of approaches used widely by the biopharmaceutical industry, involves synonymous substitutions to increase protein expression. It had long been presumed that synonymous variants, which, by definition, do not alter the primary amino acid sequence, have no effect on protein structure and function. However, a critical mass of reports suggests that synonymous codon variations may impact protein conformation. To investigate the impact of synonymous codons usage on protein expression and function, we designed an optimized coagulation factor IX (FIX) variant and used multiple methods to compare its properties to the wild-type FIX upon expression in HEK293T cells. We found that the two variants differ in their conformation, even when controlling for the difference in expression levels. Using ribosome profiling, we identified robust changes in the translational kinetics of the two variants and were able to identify a region in the gene that may have a role in altering the conformation of the protein. Our data have direct implications for codon optimization strategies, for production of recombinant proteins and gene therapies.},
doi = {10.1038/s41598-019-51984-2},
journal = {Scientific Reports},
number = 1,
volume = 9,
place = {United States},
year = {Tue Oct 29 00:00:00 EDT 2019},
month = {Tue Oct 29 00:00:00 EDT 2019}
}
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Figure 1: Properties of wild-type and codon-optimized $F$9 genes’ sequences. (a) CO $F$9 utilizes more common codons and common codon pairs. The Relative Synonymous Codon Usage (RSCU) and Relative Synonymous Codon Pair Usage (RSCPU) were calculated based on codon usage frequencies obtained from https://hive. biochemistry.gwu.edu/review/codon. The 7 codon and codonmore »
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Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling
journal, April 2009
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Works referencing / citing this record:
Ribosome profiling of HEK293T cells overexpressing codon optimized coagulation factor IX
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A Single Synonymous Variant (c.354G>A [p.P118P]) in ADAMTS13 Confers Enhanced Specific Activity
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A hotspot for enhancing insulin receptor activation revealed by a conformation-specific allosteric aptamer
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