ArticleThe Journal of biological chemistry2013
Autoactivation of thrombin precursors.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 45 citations in OpenAlex.
- PrankWeb 4: a modular web server for protein-ligand binding site prediction and downstream analysis.Nucleic acids research · 2025Article
- Lupus anticoagulant and antiprothrombin antibodies: embracing the future.Journal of thrombosis and haemostasis : JTH · 2025Review
- New insight into the traditional model of the coagulation cascade and its regulation: illustrated review of a three-dimensional view.Research and practice in thrombosis and haemostasis · 2023Article
- Cloning, Expression and Purification of Full-length Recombinant Ecarin and Comparing Its Expression and Function with Its Truncated Form.Iranian journal of pharmaceutical research : IJPR · 2022Article
- The active site region plays a critical role in NaThe Journal of biological chemistry · 2022Article
- Proteolytic activity of contact factor zymogens.Journal of thrombosis and haemostasis : JTH · 2021Review
- A Novel ELISA Assay for the Detection of Anti-Prothrombin Antibodies in Antiphospholipid Syndrome Patients at High Risk of Thrombosis.Frontiers in immunology · 2021Article
- Role of the activation peptide in the mechanism of protein C activation.Scientific reports · 2020Article
- Roles of the clip domains of two protease zymogens in the coagulation cascade in horseshoe crabs.The Journal of biological chemistry · 2020Article
- Role of the I16-D194 ionic interaction in the trypsin fold.Scientific reports · 2019Article
- Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin.Scientific reports · 2019Article
- Probing prothrombin structure by limited proteolysis.Scientific reports · 2019Article
- Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.Biochemistry · 2019Article
- Blocking the proteolytic activity of zymogen matriptase with antibody-based inhibitors.The Journal of biological chemistry · 2019Article
- Interplay between conformational selection and zymogen activation.Scientific reports · 2018Article
- Structure of prothrombin in the closed form reveals new details on the mechanism of activation.Scientific reports · 2018Article
- Structure of Coagulation Factor II: Molecular Mechanism of Thrombin Generation and Development of Next-Generation Anticoagulants.Frontiers in medicine · 2018Review
- Rational Design of Protein C Activators.Scientific reports · 2017Article
- Dual effect of histone H4 on prothrombin activation.Journal of thrombosis and haemostasis : JTH · 2016Article
- Structural Architecture of Prothrombin in Solution Revealed by Single Molecule Spectroscopy.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Trypsin-like proteases are synthesized as inactive zymogens and convert to the mature form upon activation by specific enzymes, often assisted by cofactors. Central to this paradigm is that the zymogen does not convert spontaneously to the mature enzyme, which in turn does not feed back to activate its zymogen form. In the blood, the zymogens prothrombin and prethrombin-2 require the prothrombinase complex to be converted to the mature protease thrombin, which is unable to activate prothrombin or prethrombin-2. Here, we show that replacement of key residues within the activation domain causes these zymogens to spontaneously convert to thrombin. The conversion is started by the zymogen itself, which is capable of binding ligands at the active site, and is abrogated by inactivation of the catalytic residue Ser-195. The product of autoactivation is functionally and structurally equivalent to wild-type thrombin. Zymogen autoactivation is explained by conformational selection, a basic property of the trypsin fold uncovered by structural and rapid kinetics studies. Both the zymogen and protease undergo a pre-existing equilibrium between active and inactive forms. The equilibrium regulates catalytic activity in the protease and has the potential to unleash activity in the zymogen to produce autoactivation. A new strategy emerges for the facile production of enzymes through zymogen autoactivation that is broadly applicable to trypsin-like proteases of biotechnological and clinical interest.
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Registered trials
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.