NDLI: Inhibition of antithrombin by Plasmodium falciparum histidine-rich protein II

Content Provider	PubMed Central
Author	Matthew, Ndonwi Burlingame, Oname O. Miller, Aaron S. Tollefsen, Douglas M. Broze, George J. Goldberg, Daniel E.
Copyright Year	2011
Abstract	Histidine-rich protein II (HRPII) is an abundant protein released into the bloodstream by Plasmodium falciparum, the parasite that causes the most severe form of human malaria. Here, we report that HRPII binds tightly and selectively to coagulation-active glycosaminoglycans (dermatan sulfate, heparan sulfate, and heparin) and inhibits antithrombin (AT). In purified systems, recombinant HRPII neutralized the heparin-catalyzed inhibition of factor Xa and thrombin by AT in a Zn2+-dependent manner. The observed 50% inhibitory concentration (IC50) for the HRPII neutralization of AT activity is approximately 30nM for factor Xa inhibition and 90nM for thrombin inhibition. Zn2+ was required for these reactions with a distribution coefficient (K d) of approximately 7μM. Substituting Zn2+ with Cu2+, but not with Ca2+, Mg2+, or Fe2+, maintained the HRPII effect. HRPII attenuated the prolongation in plasma clotting time induced by heparin, suggesting that HRPII inhibits AT activity by preventing its stimulation by heparin. In the microvasculature, where erythrocytes infected with P falciparum are sequestered, high levels of released HRPII may bind cellular glycosaminoglycans, prevent their interaction with AT, and thereby contribute to the procoagulant state associated with P falciparum infection.
Related Links	http://dx.doi.org/10.1182/blood-2010-12-326876
Ending Page	6354
Page Count	8
Starting Page	6347
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	23
Volume Number	117
Language	English
Publisher	American Society of Hematology
Publisher Date	2011-06-09
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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