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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-06-1818. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1818v1 101/4/1375    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bonnefoy, A. Articles by Hoylaerts, M. F. Search for Related Content PubMed PubMed Citation Articles by Bonnefoy, A. Articles by Hoylaerts, M. F. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2003, Vol. 101, No. 4, pp. 1375-1383 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Shielding the front-strand 3 of the von Willebrand factor A1 domain inhibits its binding to platelet glycoprotein Ib Arnaud Bonnefoy, Hiroshi Yamamoto, Chantal Thys, Morikazu Kito, Jos Vermylen, and Marc F. Hoylaerts From the Center for Molecular and Vascular Biology, K.U. Leuven, Leuven, Belgium; and Ajinomoto Co, Inc, Kawasaki, Japan. Platelet adhesion to damaged vessel wall and shear-induced platelet aggregation necessitate binding of the von Willebrand factor (VWF) A1 domain to platelet GPIb. Blocking this interaction represents a promising approach to the treatment of arterial thrombosis. Comparison of amino acid sequences of the VWF A1 domain in several species, expressing VWF recognized by the blocking monoclonal antibody AJvW-2, suggested 9 residues (His563, Ile566, Asp570, Ala581, Val584, Ala587, Arg616, Ala618, and Met622) to contribute to the epitope for AJvW-2 or to be part of the GPIb-binding site. Glutathione-S-transferase (GST)-human VWF A1 fusion proteins, in which these amino acids were mutated to their murine counterparts, were tested for their capacity to bind AJvW-2 or heparin, to interfere with botrocetin- or ristocetin-mediated VWF binding to GPIb, or to induce flow-dependent platelet tethering in a perfusion chamber. Thus, mutations His563Arg, Ile566Leu, Asp570Ala, and Ala587Thr, clustered on the outer surface of the A1 domain, dramatically impaired binding of AJvW-2 to A1. The His563Arg, Ile566Leu, and Asp570Ala mutations also impaired the binding of heparin, which competes with AJvW-2 for binding to A1. Perfusion studies revealed that His563, Ile566, Asp570, Arg616, and Ala618 take part in GPIb binding, their mutation-impairing platelet recruitment. In agreement with the surface distribution of VWF type 2M mutations, this study demonstrates overlapping of the epitope for AJvW-2 and the GPIb-binding site, located around the front pocket of the A1 domain and defined by strands 3, 4, and helix 3, and it provides a mechanistic basis for VWF neutralization by this antibody. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. O. Spiel, J. C. Gilbert, and B. Jilma Von Willebrand Factor in Cardiovascular Disease: Focus on Acute Coronary Syndromes Circulation, March 18, 2008; 117(11): 1449 - 1459. [Abstract] [Full Text] [PDF] A. Mazharian, S. Roger, P. Maurice, E. Berrou, M. R. Popoff, M. F. Hoylaerts, F. Fauvel-Lafeve, A. Bonnefoy, and M. Bryckaert Differential Involvement of ERK2 and p38 in Platelet Adhesion to Collagen J. Biol. Chem., July 15, 2005; 280(28): 26002 - 26010. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020