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Thromb Haemost 1998; 80(03): 499-505
DOI: 10.1055/s-0037-1615236
DOI: 10.1055/s-0037-1615236
Rapid Communications
Purification and Characterization of Kaouthiagin, a von Willebrand Factor-Binding and -Cleaving Metalloproteinase from Naja kaouthia Cobra Venom
Authors
Supported in part by Grants-in-Aid from the Japanese Ministry of Education Culture and Science (to T. M. and K. T.), Fujita Health University (to K. T. and J. H.) the Ryoichi Naito Foundation for Medical Research (to T. M.) and the Uehara Memorial Foundation (to K. T.). A part of the results has previously been presented at the 1997 conference of the American Society of Haematology (Blood 1997; 90: 466a).
Further Information
Publication History
Received
27 January 1998
Accepted after resubmission
26 May 1998
Publication Date:
08 December 2017 (online)
Summary
A von Willebrand factor (vWF)-binding and -cleaving metalloproteinase, termed “kaouthiagin”, was purified from the venom of cobra snake Naja kaouthia. Kaouthiagin is a monomer with a molecular mass of about 46 kDa and 51 kDa under non-reducing and reducing conditions, respectively, and the N-terminal amino acid sequence is homologous to high molecular mass snake venom metalloproteinases. Kaouthiagin bound to vWF in a divalent ion-independent manner, but the reduced kaouthiagin failed to interact with vWF, suggesting that the protein conformation maintained by intrachaindisulfide linkages of the molecule is essential for the binding to vWF. Neither botrocetin nor bitiscetin, vWF-binding modulators from another snake venom, interfered with the binding between kaouthiagin and vWF, but a monoclonal antibody VW92-3 specific to the N-terminal region of vWF (residues 1-910) inhibited the binding. Without affecting platelet GPIb/IX and GPIIb/IIIa, kaouthiagin specifically cleaved vWF between residues Pro-708 and Asp-709 in a divalent ion-dependent manner to diminish the multimeric structure of vWF in plasma, resulting in the loss of ristocetin-induced platelet aggregability and the collagen-binding activity of vWF. These results indicate that kaouthiagin is a unique metalloproteinase which specifically binds to and cleaves vWF at a specific site and that it will be a useful tool for functional dissection of vWF.
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