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Heparin enhances the inhibition of factor Xa by protein C inhibitor in the presence but not in the absence of Ca2+
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2009 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 5, 1094-1098 p.Article in journal (Refereed) Published
Abstract [en]

Protein C inhibitor (PCI) is a versatile serine protease inhibitor with both pro- and anticoagulant and other properties. Interactions of certain ligands with PCI, including heparin, affect its specificity for proteases. In this study, heparin was found to enhance PCI inhibition of factor Xa up to 42-fold in the presence of a physiological Ca(2+) concentration, whereas no heparin-induced activation was observed in the absence of Ca(2+). These results thus show that factor Xa adds to the group of proteases whose inhibition by PCI is enhanced by heparin and that such inhibition contributes to the anticoagulant properties of PCI by a Ca(2+)-dependent mechanism.

Place, publisher, year, edition, pages
2009. Vol. 48, no 5, 1094-1098 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-99781DOI: 10.1021/bi802138mISI: 000263047900031PubMedID: 19140680OAI: oai:DiVA.org:uu-99781DiVA: diva2:208734
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2017-12-13Bibliographically approved
In thesis
1. A New Look into Protein C Inhibitor: Posttranslational Modifications and their Functions
Open this publication in new window or tab >>A New Look into Protein C Inhibitor: Posttranslational Modifications and their Functions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The influences of posttranslational modifications on the functions of the versatile serpin protein C inhibitor (PCI) were studied. PCI is a serine protease inhibitor that is expressed in many tissues and secreted to various fluids in human, including blood plasma, seminal plasma, and urine. PCI in blood can act both as an anticoagulant and a procoagulant and is believed to play a role in pathogen defence. PCI in reproductive tissues is believed to regulate human reproduction at several steps, including the fertilization process. Due to the broad protease specificity and the contradictory activities, the physiological role of PCI is elusive. In this work the inhibitor was purified from blood and seminal plasma by immunoaffinity chromatography. Blood-derived PCI was found to be highly heterogeneous, due to variations in posttranslational modifications. The occupancy and structures of N- and O-glycans attached to blood plasma PCI and N-glycans of seminal plasma PCI were determined by mass spectrometry. An O-glycosylation site at Thr 20 was identified in PCI derived from blood. N-glycan structures of PCI isolated from blood and seminal plasma differed markedly, demonstrating that they are expressed in a tissue-specific manner. Proteolytic processing also appeared to be tissue-specific, since N-terminally cleaved PCI was found in PCI isolated both from blood and seminal plasma, but the length of the lacking segment differed. The effects of the N-linked glycans and the N-terminus of PCI on protease inhibition were determined using enzymatic measurements with chromogenic substrates. The N-glycans and the N-terminus had different effects on the inhibition of thrombin, factor Xa and prostate specific antigen, demonstrating that posttranslational modifications of PCI affect its functional specificity. These findings enhance the understanding of the regulation of the various functions of PCI and may potentially be used for the production of specialized PCI variants for medical purposes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 601
Keyword
Protein C inhibitor, posttranslational modifications, N-glycan, O-glycan, mass spectrometry, factor Xa, thrombin, prostate specific antigen
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-131126 (URN)978-91-554-7901-5 (ISBN)
Public defence
2010-11-05, C10:301, BMC, Husarg. 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2010-10-15 Created: 2010-09-23 Last updated: 2010-10-22Bibliographically approved

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