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dc.contributor.authorKassaar, Omar
dc.contributor.authorSchwarz-Linek, Ulrich
dc.contributor.authorBlindauer, Claudia A
dc.contributor.authorStewart, Alan J.
dc.identifier.citationKassaar , O , Schwarz-Linek , U , Blindauer , C A & Stewart , A J 2015 , ' Plasma free fatty acid levels influence Zn 2+ -dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albumin ' , Journal of Thrombosis and Haemostasis , vol. 13 , no. 1 , pp. 101-110 .
dc.identifier.otherPURE: 155889155
dc.identifier.otherPURE UUID: c72368ca-454f-41be-a533-a33de0054d29
dc.identifier.otherScopus: 84920935932
dc.identifier.otherWOS: 000347970900014
dc.identifier.otherORCID: /0000-0003-0526-223X/work/40714972
dc.identifier.otherORCID: /0000-0003-4580-1840/work/60195807
dc.description.abstractBackground: Histidine-rich glycoprotein (HRG) regulates coagulation, through its ability to bind and neutralize heparins. HRG associates with zinc ions (Zn2+) to stimulate HRG-heparin complex formation. Under normal conditions the majority of plasma Zn2+ associates with human serum albumin (HSA). However, free fatty acids (FFA) allosterically disrupt Zn2+ binding to HSA. Thus high levels of circulatory FFA, as are associated with diabetes, obesity and cancer, may increase the proportion of plasma Zn2+ associated with HRG contributing to an increased risk of thrombotic disease. Objectives: The aims were to characterize Zn2+ binding by HRG, examine the influence FFA have on Zn2+ binding by HSA and establish whether FFA-mediated displacement of Zn2+ from HSA may influence HRG-heparin complex formation. Methods: Zn2+ binding to HRG and to HSA in the presence of different FFA (myristate) concentrations were examined by isothermal titration calorimetry (ITC) and the formation of HRG-heparin complexes in the presence of different Zn2+ concentrations by both ITC and an ELISA-based assay. Results and conclusions: We reveal that HRG possesses 10 Zn2+ sites (K´=1.63 x 105) and that cumulative binding of FFA to HSA perturbed its ability to bind Zn2+. Also Zn2+ binding was shown to increase the affinity by which HRG interacts with unfractionated heparins but has no effect upon its interaction with low molecular weight heparin (ca. 6850 kDa). Speciation modeling of plasma Zn2+ based upon the data obtained suggests that FFA-mediated displacement of Zn2+ from serum albumin would be likely to contribute to the development of thrombotic complications in individuals with high plasma FFA levels.
dc.relation.ispartofJournal of Thrombosis and Haemostasisen
dc.rights© 2015. The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.en
dc.subjectFatty acidsen
dc.subjectHistidine-rich glycoproteinen
dc.subjectPlasma albuminen
dc.subjectR Medicineen
dc.titlePlasma free fatty acid levels influence Zn2+-dependent histidine-rich glycoprotein-heparin interactions via an allosteric switch on serum albuminen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Institute of Behavioural and Neural Sciencesen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.description.statusPeer revieweden

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