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Redox control of beta(2) -glycoprotein I-von Willebrand factor interaction by thioredoxin-1


Summary. Background: beta(2) -Glycoprotein I (beta(2) GPI) is an abundant plasma protein that is closely linked to blood clotting, as it interacts with various protein and cellular components of the coagulation system. However, the role of beta(2) GPI in thrombus formation is unknown. We have recently shown that beta(2) GPI is susceptible to reduction by the thiol oxidoreductases thioredoxin-1 and protein disulfide isomerase, and that reduction of beta(2) GPI can take place on the platelet surface. Methods: beta(2) GPI, reduced by thioredoxin-1, was labeled with the selective sulfhydryl probe N(a) -(3-maleimidylpropionyl)biocytin and subjected to mass spectrometry to identify the specific cysteines involved in the thiol exchange reaction. Binding assays were used to examine the affinity of reduced beta(2) GPI for von Willebrand factor (VWF) and the effect of reduced beta2GPI on glycoprotein (GP)Ibalpha binding to VWF. Platelet adhesion to ristocetin-activated VWF was studied in the presence of reduced beta(2) GPI. Results: We demonstrate that the Cys288-Cys326 disulfide in domain V of beta(2) GPI is the predominant disulfide reduced by thioredoxin-1. Reduced beta(2) GPI in vitro displays increased binding to VWF that is dependent on disulfide bond formation. beta(2) GPI reduced by thioredoxin-1, in comparison with non-reduced beta(2) GPI, leads to increased binding of GPIbalpha to VWF and increased platelet adhesion to activated VWF. Conclusions: Given the importance of thiol oxidoreductases in thrombus formation, we provide preliminary evidence that the thiol-dependent interaction of beta(2) GPI with VWF may contribute to the redox regulation of platelet adhesion.

Type Journal
ISBN 1538-7836 (Electronic) 1538-7836 (Linking)
Authors Passam, F. H.; Rahgozar, S.; Qi, M.; Raftery, M. J.; Wong, J. W.; Tanaka, K.; Ioannou, Y.; Zhang, J. Y.; Gemmell, R.; Qi, J. C.; Giannakopoulos, B.; Hughes, W. E.; Hogg, P. J.; Krilis, S. A.;
Garvan Authors Dr William Hughes
Published Date 2010-01-01 00:00:00
Published Volume 8
Published Issue 8
Published Pages 1754-62
Status Published In-print
OpenAccess Link Passam et al JTH.pdf