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J. Biol. Chem., Vol. 279, Issue 48, 50267-50273, November 26, 2004

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The Heparin Binding Properties of Heparin Cofactor II Suggest an Antithrombin-like Activation Mechanism^*

Denis O'Keeffe, Steven T. Olson, Nijole Gasiunas¶, John Gallagher¶, Trevor P. Baglin, and James A. Huntington||

From the University of Cambridge, Department of Haematology, Division of Structural Medicine, Thrombosis Research Unit, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 2XY, United Kingdom, the ^¶Medical Oncology Department, University of Manchester, Manchester M20 4BX, United Kingdom, and the Center for Molecular Biology of Oral Disease, University of Illinois at Chicago, Chicago, Illinois 60612

The serpin heparin cofactor II (HCII) is a glycosaminoglycan-activated inhibitor of thrombin that circulates at a high concentration in the blood. The antithrombotic effect of heparin, however, is due primarily to the specific interaction of a fraction of heparin chains with the related serpin antithrombin (AT). What currently prevents selective therapeutic activation of HCII is the lack of knowledge of the determinants of glycosaminoglycan binding specificity. In this report we investigate the heparin binding properties of HCII and conclude that binding is nonspecific with a minimal heparin length of 13 monosaccharide units required and affinity critically dependent on ionic strength. Rapid kinetics of heparin binding indicate an induced fit mechanism that involves a conformational change in HCII. Thus, HCII binds to heparin in a manner analogous to the interaction of AT with low affinity heparin. A fully allosteric 2000-fold heparin activation of thrombin inhibition by HCII is demonstrated for heparin chains up to 26 monosaccharide units in length. We conclude that the heparin-binding mechanism of HCII is closely analogous to that of AT and that the induced fit mechanism suggests the potential design or discovery of specific HCII agonists.

Received for publication, August 2, 2004 , and in revised form, September 7, 2004.

^* This work was supported by grants from the British Heart Foundation (to D. O.) and the Medical Research Council and by National Institutes of Health Grants HL68629 (to J. A. H.) and HL39888 and HL64013 (to S. T. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 44-1223-763230; Fax: 44-1223-336827; E-mail: jah52{at}cam.ac.uk.

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