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

Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the gene, encoding a plasma protease r...

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Published in:	International journal of molecular sciences Vol. 20; no. 22; p. 5734
Main Authors:	Hunt, Ryan, Hettiarachchi, Gaya, Katneni, Upendra, Hernandez, Nancy, Holcomb, David, Kames, Jacob, Alnifaidy, Redab, Lin, Brian, Hamasaki-Katagiri, Nobuko, Wesley, Aaron, Kafri, Tal, Morris, Christina, Bouché, Laura, Panico, Maria, Schiller, Tal, Ibla, Juan, Bar, Haim, Ismail, Amra, Morris, Howard, Komar, Anton, Kimchi-Sarfaty, Chava
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 15-11-2019 MDPI
Subjects:	adamts13 ADAMTS13 Protein - genetics Bioengineering Circular Dichroism codon usage Disease Efficiency Experiments Genetic diversity Genomes HEK293 Cells Humans Liver Mammals Mass Spectrometry Mutation post-translational modifications Protein expression Protein folding Protein Processing, Post-Translational Protein structure Proteins ribosome profiling Ribosomes - genetics Ribosomes - metabolism specific activity synonymous variant Translation ADAMTS13 ribosome profiling specific activity translation post-translational modifications synonymous variant codon usage
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Abstract	Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure.
AbstractList	Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the ADAMTS13 gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure. [...]occurring genetic variants that augment protein expression hold promise for bioengineering purposes, but a thorough evaluation of their effects on physical and functional properties of the encoded protein is required. [...]in the last few years more than 50 diseases were reported to be associated with a single synonymous mutation in the disease associated gene [4]. [...]c.354G>A variant represent a unique example in this regard in which the synonymous variation produces a substantial positive contribution to protein expression levels [18]. [...]we decided to extensively characterize c.354G>A variant and compare its properties to that of the WT ADAMTS13. Since the liver is the major source of ADAMTS13 [26], we have also calculated RSCU values based on liver tissue specific codon usage frequencies. Overall, these results show that c.354G>A substitution resulted in the introduction of frequently used codon/codon pair(s) relative to WT sequence, and this in turn could have potentially led to enhanced translation of the c.354G>A [p.P118P] variant. Since altered translation kinetics can affect co-translational folding and protein conformation [27,28], we have proceeded to assess the Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the ADAMTS13 gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure. Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex vivo (~120% in comparison to wild-type) from a synonymous polymorphism variant, c.354G>A [p.P118P], of the gene, encoding a plasma protease responsible for von Willebrand Factor (VWF) degradation. In the current study, we investigated the potential mechanism(s) behind the increased protein expression levels from this variant and its effect on ADAMTS13 physico-chemical properties. Cell-free assays showed enhanced translation of the c.354G>A variant and the analysis of codon usage characteristics suggested that introduction of the frequently used codon/codon pair(s) may have been potentially responsible for this effect. Limited proteolysis, however, showed no substantial influence of altered translation on protein conformation. Analysis of post-translational modifications also showed no notable differences but identified three previously unreported glycosylation markers. Despite these similarities, p.P118P variant unexpectedly showed higher specific activity. Structural analysis using modeled interactions indicated that subtle conformational changes arising from altered translation kinetics could affect interactions between an exosite of ADAMTS13 and VWF resulting in altered specific activity. This report highlights how a single synonymous nucleotide variation can impact cellular expression and specific activity in the absence of measurable impact on protein structure.
Author	Schiller, Tal Ibla, Juan Holcomb, David Morris, Howard Lin, Brian Hamasaki-Katagiri, Nobuko Morris, Christina Hettiarachchi, Gaya Katneni, Upendra Kames, Jacob Hernandez, Nancy Kimchi-Sarfaty, Chava Wesley, Aaron Bar, Haim Hunt, Ryan Ismail, Amra Komar, Anton Alnifaidy, Redab Bouché, Laura Kafri, Tal Panico, Maria
AuthorAffiliation	7 Departments of Cardiac Surgery and Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA 2 Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA 5 Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK 4 BioPharmaSpec Ltd., St. Saviour JE2 7LA, UK or or 6 Present Address: Antikor Biopharma Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage SG1 2FX, UK 9 Center for Gene Regulation in Health and Disease, Department of Biological, Geological & Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA 8 Department of Statistics, University of Connecticut, Storrs, CT 06269, USA 1 Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, MD 20993, USA 3 Present Address: Department of Emergency Medicine,
AuthorAffiliation_xml	– name: 8 Department of Statistics, University of Connecticut, Storrs, CT 06269, USA – name: 6 Present Address: Antikor Biopharma Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage SG1 2FX, UK – name: 7 Departments of Cardiac Surgery and Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA – name: 5 Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK – name: 1 Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, MD 20993, USA – name: 9 Center for Gene Regulation in Health and Disease, Department of Biological, Geological & Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA – name: 4 BioPharmaSpec Ltd., St. Saviour JE2 7LA, UK or or – name: 2 Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA – name: 3 Present Address: Department of Emergency Medicine, Banner University Medical Center, The University of Arizona, Tucson, AZ 85724, USA
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Christina organization: BioPharmaSpec Ltd., St. Saviour JE2 7LA, UK – sequence: 13 givenname: Laura surname: Bouché fullname: Bouché, Laura organization: Present Address: Antikor Biopharma Ltd., Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage SG1 2FX, UK – sequence: 14 givenname: Maria surname: Panico fullname: Panico, Maria organization: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK – sequence: 15 givenname: Tal surname: Schiller fullname: Schiller, Tal organization: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, MD 20993, USA – sequence: 16 givenname: Juan surname: Ibla fullname: Ibla, Juan organization: Departments of Cardiac Surgery and Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA – sequence: 17 givenname: Haim orcidid: 0000-0002-5496-9699 surname: Bar fullname: Bar, Haim organization: Department of Statistics, University of Connecticut, Storrs, CT 06269, USA – sequence: 18 givenname: Amra surname: Ismail fullname: Ismail, Amra organization: Center for Gene Regulation in Health and Disease, Department of Biological, Geological & Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA – sequence: 19 givenname: Howard surname: Morris fullname: Morris, Howard organization: Department of Life Sciences, Imperial College London, South Kensington Campus, London SW7 2AZ, UK – sequence: 20 givenname: Anton orcidid: 0000-0003-4188-0633 surname: Komar fullname: Komar, Anton organization: Center for Gene Regulation in Health and Disease, Department of Biological, Geological & Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA – sequence: 21 givenname: Chava surname: Kimchi-Sarfaty fullname: Kimchi-Sarfaty, Chava organization: Hemostasis Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation & Research, US FDA, Silver Spring, MD 20993, USA
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Keywords	ADAMTS13 ribosome profiling specific activity translation post-translational modifications synonymous variant codon usage
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Notes	These authors contributed equally to this work.
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Snippet	Synonymous variants within coding regions may influence protein expression and function. We have previously reported increased protein expression levels ex... [...]occurring genetic variants that augment protein expression hold promise for bioengineering purposes, but a thorough evaluation of their effects on...
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SubjectTerms	adamts13 ADAMTS13 Protein - genetics Bioengineering Circular Dichroism codon usage Disease Efficiency Experiments Genetic diversity Genomes HEK293 Cells Humans Liver Mammals Mass Spectrometry Mutation post-translational modifications Protein expression Protein folding Protein Processing, Post-Translational Protein structure Proteins ribosome profiling Ribosomes - genetics Ribosomes - metabolism specific activity synonymous variant Translation
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Title	A Single Synonymous Variant (c.354G>A [p.P118P]) in ADAMTS13 Confers Enhanced Specific Activity
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