ArticleThe Journal of biological chemistry2008
Kinetic characterization of the protein Z-dependent protease inhibitor reaction with blood coagulation factor Xa.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 50 citations in OpenAlex.
- Design, Synthesis, and In Vitro and In Silico Study of New Hybrid 1-(2-(4-Arylthiazol-2-yl)hydrazineylidene)-5,6-dihydro-4Molecules (Basel, Switzerland) · 2025Article
- Tapping Into the Natural PZ-Independent Anticoagulant Function of ZPI to Inhibit Thrombosis With Minimal Effect on Hemostasis.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Loss of protein C vs protein S results in discrepant thrombotic phenotypes.Blood advances · 2025Article
- Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4Molecules (Basel, Switzerland) · 2024Article
- Heparin activation of protein Z-dependent protease inhibitor (ZPI) allosterically blocks protein Z activation through an extended heparin-binding site.The Journal of biological chemistry · 2022Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Engineering a protein Z-dependent protease inhibitor (ZPI) mutant as a novel antagonist of ZPI anticoagulant function for hemophilia treatment.Journal of thrombosis and haemostasis : JTH · 2019Article
- Protein Z-dependent protease inhibitor (ZPI) is a physiologically significant inhibitor of prothrombinase function.The Journal of biological chemistry · 2019Article
- Suppressing protein Z-dependent inhibition of factor Xa improves coagulation in hemophilia A.Journal of thrombosis and haemostasis : JTH · 2019Article
- Lipid oxidation inactivates the anticoagulant function of protein Z-dependent protease inhibitor (ZPI).The Journal of biological chemistry · 2017Article
- Article
- Low protein Z plasma level is a risk factor for acute myocardial infarction in coronary atherosclerosis disease patients.Thrombosis research · 2016Article
- Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance.The Biochemical journal · 2016Review
- The role of protein Z and protein Z-dependent protease inhibitor polymorphisms in the development of prosthetic heart valve thrombosis.Anatolian journal of cardiology · 2016Article
- Phosphatidylserine and Phosphatidylethanolamine Bind to Protein Z Cooperatively and with Equal Affinity.PloS one · 2016Article
- Thermodynamic and kinetic characterization of the protein Z-dependent protease inhibitor (ZPI)-protein Z interaction reveals an unexpected role for ZPI Lys-239.The Journal of biological chemistry · 2015Article
- Characterization of the protein Z-dependent protease inhibitor interactive-sites of protein Z.Biochimica et biophysica acta · 2014Article
- Amblyomma americanum tick saliva serine protease inhibitor 6 is a cross-class inhibitor of serine proteases and papain-like cysteine proteases that delays plasma clotting and inhibits platelet aggregation.Insect molecular biology · 2013Article
- Residues of the 39-loop restrict the plasma inhibitor specificity of factor IXa.The Journal of biological chemistry · 2013Article
- Structural basis for catalytic activation of protein Z-dependent protease inhibitor (ZPI) by protein Z.Blood · 2012Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Protein Z-dependent protease inhibitor (ZPI) is a recently identified member of the serpin superfamily that functions as a cofactor-dependent regulator of blood coagulation factors Xa (FXa) and XIa. Here we show that ZPI and its cofactor, protein Z (PZ), inhibit procoagulant membrane-bound factor Xa by the branched pathway acyl-intermediate trapping mechanism used by other serpins, but with significant variations of this mechanism that are unique to ZPI. Rapid kinetic analyses showed that the reaction proceeded by the initial assembly of a membrane-associated PZ-ZPI-FXa Michaelis complex (K(M) 53+/-5 nM) followed by conversion to a stable ZPI-FXa complex (k(lim) 1.2+/-0.1 s(-1)). Cofactor premixing experiments together with independent kinetic analyses of ZPI-PZ and factor Xa-PZ-membrane complex formation suggested that assembly of the Michaelis complex through either ZPI-PZ-lipid or factor Xa-PZ-lipid intermediates was rate-limiting. Reaction stoichiometry analyses and native PAGE showed that for every factor Xa molecule inhibited by ZPI, two serpin molecules were cleaved. Native PAGE and immunoblotting showed that PZ dissociated from ZPI once ZPI forms a stable complex with FXa, and kinetic analyses confirmed that PZ acted catalytically to accelerate the membrane-dependent ZPI-factor Xa reaction. The ZPI-FXa complex was only transiently stable and dissociated with a rate constant that showed a bell-shaped pH dependence indicative of participation of factor Xa active-site residues. The complex was detectable by SDS-PAGE when denatured at low pH, consistent with it being a kinetically trapped covalent acyl-intermediate. Together our findings show that ZPI functions like other serpins to regulate the activity of FXa but in a manner uniquely dependent on protein Z, procoagulant membranes, and pH.
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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.