Abstract
von Willebrand factor (VWF) performs its hemostatic functions through binding to various proteins. The A1 domain of VWF contains binding sites of not only physiologically important ligands, but also exogenous modulators that induce VWF-platelet aggregation. Sulfatides, 3-sulfated galactosyl ceramides, that are expressed on oligodendrocytes, renal tubular cells, certain tumor cells and platelets, have been suggested to interact with VWF under some pathological conditions. The binding of VWF to sulfatide requires the A1 domain, but its binding sites have not been precisely identified. Here, we report that alanine mutations at Arg1392, Arg1395, Arg1399 and Lys1423 led to decreased VWF–sulfatide binding. These sites have been reported to be the binding sites for platelet membrane glycoprotein (GP) Ib and/or snake venom botrocetin, and, interestingly, are identical to the monoclonal antibody (mAb) NMC4 epitope previously reported to inhibit the VWF-GPIb interaction. We observed that NMC4 also inhibited VWF interaction with sulfatides in a dose-dependent manner. Thus, we conclude that VWF binding sites of sulfatide overlap those of platelet GPIb and botrocetin.
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Acknowledgments
We are grateful to Ms. Chika Wakamatsu for performing excellent, skilled techniques in molecular biology. Particular gratitude is expressed to Dr. Dominique Meyer for providing information on mAb 701 and B724. We also thank Dr. Wayne Albers for his technical advice regarding the 3D structure, and are grateful to Dr. Sashi Kesavapany for the helpful suggestions.
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Nakayama, T., Matsushita, T., Yamamoto, K. et al. Identification of amino acid residues responsible for von Willebrand factor binding to sulfatide by charged-to-alanine-scanning mutagenesis. Int J Hematol 87, 363–370 (2008). https://doi.org/10.1007/s12185-008-0065-8
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DOI: https://doi.org/10.1007/s12185-008-0065-8