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J. Biol. Chem., Vol. 283, Issue 33, 22498-22504, August 15, 2008

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Antihemostatic Activity of Human Granzyme B Mediated by Cleavage of von Willebrand Factor^*

Marguerite S. Buzza, Jennifer M. Dyson, Hiuwan Choi, Elizabeth E. Gardiner^¶, Robert K. Andrews^¶, Dion Kaiserman, Christina A. Mitchell, Michael C. Berndt^¶, Jing-Fei Dong, and Phillip I. Bird¹

From the Department of Biochemistry and Molecular Biology, Monash University, Clayton 3800, Victoria, Australia, Thrombosis Research Section, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, and the ^¶Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne 3004, Victoria, Australia

The cytotoxic lymphocyte protease granzyme B (GrB) is elevated in the plasma of individuals with diseases that elicit a cytotoxic lymphocyte-mediated immune response. Given the recently recognized ability of GrB to cleave extracellular matrix proteins, we examined the effect of GrB on the pro-hemostatic molecule von Willebrand factor (VWF). GrB delays ristocetin-induced platelet aggregation and inhibits platelet adhesion and spreading on immobilized VWF under static conditions. It efficiently cleaves VWF at two sites within the A1–3 domains that are essential for the VWF-platelet interaction. Like the VWF regulatory proteinase ADAMTS-13, GrB-mediated cleavage is dependent upon VWF conformation. In vitro, GrB cannot cleave the VWF conformer found in solution, but cleavage is induced when VWF is artificially unfolded or presented as a matrix. GrB cleaves VWF with comparable efficiency to ADAMTS-13 and rapidly processes ultra-large VWF multimers released from activated endothelial cells under physiological shear. GrB also cleaves the matrix form of fibrinogen at several sites. These studies suggest extracellular GrB may help control localized coagulation during inflammation.

Received for publication, November 6, 2007 , and in revised form, June 20, 2008.

^* This work was supported by the National Health and Medical Research Council of Australia. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed. Tel.: 61-3-99053771; Fax: 61-3-99053726; E-mail: phil.bird{at}med.monash.edu.au.

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