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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Yee, Andrew Ginsburg, David Siemieniak, David Kondrashov, Fyodor A. Meng, Fan Desch, Karl C. Kretz, Colin A. Dai, Manhong Soylemez, Onuralp Tomberg, Kärt |
| Description | Author Affiliation: Kretz CA ( Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109); Dai M ( Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109); Soylemez O ( Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Barcelona, Spain 08003); Yee A ( Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109); Desch KC ( Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109); Siemieniak D ( Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109); Tomberg K ( Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109); Kondrashov FA ( Bioinformatics and Genomics Programme, Centre for Genomic Regulation, Barcelona, Spain 08003); Meng F ( Department of Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109); Ginsburg D ( Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109); |
| Abstract | Proteases play important roles in many biologic processes and are key mediators of cancer, inflammation, and thrombosis. However, comprehensive and quantitative techniques to define the substrate specificity profile of proteases are lacking. The metalloprotease ADAMTS13 regulates blood coagulation by cleaving von Willebrand factor (VWF), reducing its procoagulant activity. A mutagenized substrate phage display library based on a 73-amino acid fragment of VWF was constructed, and the ADAMTS13-dependent change in library complexity was evaluated over reaction time points, using high-throughput sequencing. Reaction rate constants (kcat/KM) were calculated for nearly every possible single amino acid substitution within this fragment. This massively parallel enzyme kinetics analysis detailed the specificity of ADAMTS13 and demonstrated the critical importance of the P1-P1' substrate residues while defining exosite binding domains. These data provided empirical evidence for the propensity for epistasis within VWF and showed strong correlation to conservation across orthologs, highlighting evolutionary selective pressures for VWF. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 30 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | ADAM Proteins Chemistry High-Throughput Nucleotide Sequencing Amino Acid Sequence Binding Sites Genetics Blood Coagulation Cloning, Molecular Epistasis, Genetic Kinetics Molecular Sequence Data Mutagenesis Mutation Peptide Library Protein Binding Proteolysis Substrate Specificity Von Willebrand Factor Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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