ArticleProceedings of the National Academy of Sciences of the United States of America2015
Massively parallel enzyme kinetics reveals the substrate recognition landscape of the metalloprotease ADAMTS13.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- PhageScout: Protease Cleavage Site Prediction Using an Experimental Substrate Phage Display Motif-Based Approach.International journal of molecular sciences · 2026Article
- Deep Protease Profiling to Define the Substrate Specificity of ADAMTS Proteases.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Development of a protease-resistant ADAMTS13 to improve stability against proteolytic degradation.Blood advances · 2025Article
- Venous thromboembolic disease genetics: from variants to function.Journal of thrombosis and haemostasis : JTH · 2024Review
- Article
- Mechanisms of ADAMTS13 regulation.Journal of thrombosis and haemostasis : JTH · 2022Review
- Deep mutational scanning and massively parallel kinetics of plasminogen activator inhibitor-1 functional stability to probe its latency transition.The Journal of biological chemistry · 2022Article
- Phage display broadly identifies inhibitor-reactive regions in von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2021Article
- Deep mutational scanning of the plasminogen activator inhibitor-1 functional landscape.Scientific reports · 2021Article
- Quantitative profiling of protease specificity.PLoS computational biology · 2021Article
- Expanding the Chemical Diversity of Genetically Encoded Libraries.ACS combinatorial science · 2020Article
- ADAMTS proteases in cardiovascular physiology and disease.Open biology · 2020Review
- Exploring the Post-translational Enzymology of PaaA by mRNA Display.Journal of the American Chemical Society · 2020Article
- MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect.Genome biology · 2019Article
- Crystal structure and substrate-induced activation of ADAMTS13.Nature communications · 2019Article
- Article
- High throughput protease profiling comprehensively defines active site specificity for thrombin and ADAMTS13.Scientific reports · 2018Article
- ADAMTS-13 and von Willebrand factor: a dynamic duo.Journal of thrombosis and haemostasis : JTH · 2018Review
- Family-Specific Variants and the Limits of Human Genetics.Trends in molecular medicine · 2016Review
- Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity.Journal of thrombosis and haemostasis : JTH · 2016Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.