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J. Biol. Chem., Vol. 281, Issue 8, 4699-4707, February 24, 2006

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Shielding of the A1 Domain by the D'D3 Domains of von Willebrand Factor Modulates Its Interaction with Platelet Glycoprotein Ib-IX-V^*

Hans Ulrichts¹², Miklós Udvardy¹, Peter J. Lenting^¶, Inge Pareyn, Nele Vandeputte, Karen Vanhoorelbeke², and Hans Deckmyn³

From the Laboratory for Thrombosis Research, Interdisciplinary Research Center, Katholieke Universiteit Leuven Campus Kortrijk, B-8500 Kortrijk, Belgium, Department of Clinical Biochemistry and Molecular Pathology, University Debrecen, Faculty of Medicine, H-4012 Debrecen, Hungary, and ^¶Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands

Soluble von Willebrand factor (VWF) has a low affinity for platelet glycoprotein (GP) Ib and needs immobilization and/or high shear stress to enable binding of its A1 domain to the receptor. The previously described anti-VWF monoclonal antibody 1C1E7 enhances VWF/GPIb binding and recognizes an epitope in the amino acids 764–1035 region in the N-terminal D'D3 domains. In this study we demonstrated that the D'D3 region negatively modulates the VWF/GPIb-IX-V interaction; (i) deletion of the D'D3 region in VWF augmented binding to GPIb, suggesting an inhibitory role for this region, (ii) the isolated D'D3 region inhibited the GPIb interaction of a VWF deletion mutant lacking this region, indicating that intramolecular interactions limit the accessibility of the A1 domain, (iii) using a panel of anti-VWF monoclonal antibodies, we next showed that the D'D3 region is in close proximity with the A1 domain in soluble VWF but not when VWF was immobilized; (iv) destroying the epitope of 1C1E7 resulted in a mutant VWF with an increased affinity for GPIb. Our results support a model of domain translocation in VWF that allows interaction with GPIb. The suggested shielding interaction of the A1 domain by the D'D3 region then becomes disrupted by VWF immobilization.

Received for publication, December 14, 2005 , and in revised form, December 22, 2005.

^* This work was supported in part by K.U. Leuven Grant GOA/2004/00, European Union-Research Training Network HPRN-CT-2002-00253, and a bilateral collaboration grant between Flanders and Hungary (BIL/04/35). 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.

¹ Both authors contributed equally to this work.

² Supported by postdoctoral fellowships of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.

³ To whom correspondence should be addressed: Laboratory for Thrombosis Research, KU Leuven, Campus Kortrijk, E. Sabbelaan 53, B-8500 Kortrijk, Belgium. Tel.: 32-56246422; Fax: 32-56246997; E-mail: Hans.Deckmyn{at}kuleuven-kortrijk.be.

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