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J. Biol. Chem., Vol. 280, Issue 44, 36729-36736, November 4, 2005

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The Binding Site in ₂-Glycoprotein I for ApoER2' on Platelets Is Located in Domain V^*

Menno van Lummel1, Maarten T. T. Pennings1, Ronald H. W. M. Derksen¶, Rolf T. Urbanus, Bianca C. H. Lutters||, Niels Kaldenhoven**, and Philip G. de Groot2

From the Departments of Haematology and Rheumatology and ^¶Clinical Immunology, University Medical Center, 3508GA Utrecht, Institute of Biomembranes, Utrecht University, 3508GA Utrecht, the ^**Department of Crystal and Structural Chemistry, ABC Protein Expression Center, Utrecht University, 3584 CH Utrecht, and the ^||Division of Biopharmaceutics, Center for Drug Research, Leiden University, 2300 RA Leiden, The Netherlands

The antiphospholipid syndrome is caused by autoantibodies directed against ₂-glycoprotein I (₂GPI). Dimerization of ₂GPI results in an increased platelet deposition to collagen. We found that apolipoprotein E receptor 2' (apoER2'), a member of the low density lipoprotein receptor family, is involved in activation of platelets by dimeric ₂GPI. To identify which domain of dimeric ₂GPI interacts with apoER2', we have constructed domain deletion mutants of dimeric ₂GPI, lacking domain I (I), II (II), or V (V), and a mutant with a W316S substitution in the phospholipid (PL)-insertion loop of domain V. I and II prolonged the clotting time, as did full-length dimeric ₂GPI; V had no effect on the clotting time. Second, I and II bound to anionic PL, comparable with full-length dimeric ₂GPI. V and the W316S mutant bound with decreased affinity to anionic PL. Platelet adhesion to collagen increased significantly when full-length dimeric ₂GPI, I, or II (mean increase 150%) were added to whole blood. No increase was found with plasma ₂GPI, V, or the W316S mutant. Immunoprecipitation indicated that full-length dimeric ₂GPI, I, II, and the W316S mutant can interact with apoER2' on platelets. V did not associate with apoER2'. We conclude that domain V is involved in both binding ₂GPI to anionic PL and in interaction with apoER2' and subsequent activation of platelets. The binding site in ₂GPI for interaction with apoER2' does not overlap with the hydrophobic insertion loop in domain V.

Received for publication, April 18, 2005 , and in revised form, July 25, 2005.

^* This work was supported by Grant Zon-MW:902-26-290 from the Netherlands Organization for Health Research and Development and by Grant 2003B74 from the Netherlands Heart Foundation. 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 To whom correspondence should be addressed: Thrombosis and Haemostasis Laboratory, G.03.647, Dept. of Haematology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: 31-30-2507770; Fax: 31-30-2511893; E-mail: ph.g.degroot{at}azu.nl.

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