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J. Biol. Chem., Vol. 282, Issue 49, 35712-35721, December 7, 2007

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The ADAM10 Prodomain Is a Specific Inhibitor of ADAM10 Proteolytic Activity and Inhibits Cellular Shedding Events^*

Marcia L. Moss¹, Martha Bomar, Qian Liu, Harvey Sage, Peter Dempsey^¶, Patricia M. Lenhart^¶, Patricia A. Gillispie^¶, Alexander Stoeck^¶, Dirk Wildeboer^||, Jörg W. Bartsch^||, Ralf Palmisano^**, and Pei Zhou²

From the BioZyme Incorporated, Apex, North Carolina 27523, the Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, the ^¶Departments of Pediatrics and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, the ^||Department of Biochemistry, King's College London, London SE1 9NH, United Kingdom, and the ^**Faculty of Biology, University of Bielefeld, 33615 Bielefeld, Germany

ADAM10 is a disintegrin metalloproteinase that processes amyloid precursor protein and ErbB ligands and is involved in the shedding of many type I and type II single membrane-spanning proteins. Like tumor necrosis factor--converting enzyme (TACE or ADAM17), ADAM10 is expressed as a zymogen, and removal of the prodomain results in its activation. Here we report that the recombinant mouse ADAM10 prodomain, purified from Escherichia coli, is a potent competitive inhibitor of the human ADAM10 catalytic/disintegrin domain, with a K_i of 48 nM. Moreover, the mouse ADAM10 prodomain is a selective inhibitor as it only weakly inhibits other ADAM family proteinases in the micromolar range and does not inhibit members of the matrix metalloproteinase family under similar conditions. Mouse prodomains of TACE and ADAM8 do not inhibit their respective enzymes, indicating that ADAM10 inhibition by its prodomain is unique. In cell-based assays we show that the ADAM10 prodomain inhibits betacellulin shedding, demonstrating that it could be of potential use as a therapeutic agent to treat cancer.

Received for publication, April 17, 2007 , and in revised form, September 20, 2007.

^* This work was supported by the Whitehead Institute, King's College London (to J. W. B.), by National Institutes of Health T32 Training Grant, by National Institutes of Health Grants DK59778 and DK63363, and by a Crohns and Colitis Foundation of America grant (to P. J. D.). 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 To whom correspondence may be addressed: BioZyme Inc., 1513 Old White Oak Church Rd., Apex, NC 27523. Tel.: 919-362-1339; Fax: 919-362-1339; E-mail: mmoss{at}biozyme-inc.com. ²To whom correspondence may be addressed: Dept. of Biochemistry, Duke University Medical Center, Rm. 242, Nanaline Bldg., Research Dr., Durham, NC 27710. Tel.: 919-668-6409; Fax: 919-684-8885; E-mail: peizhou{at}biochem.duke.edu.

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