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A more recent version of this article appeared on December 7, 2007
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M703231200v1
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Papers In Press, published online ahead of print September 25, 2007
J. Biol. Chem, 10.1074/jbc.M703231200
Submitted on April 17, 2007
Revised on September 20, 2007
Accepted on September 25, 2007

The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events

Marcia L. Moss, 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 Zhou

BioZyme Inc, Apex, NC 27523

Corresponding Author: moss0610{at}yahoo.com

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-a 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 E. coli, is a potent competitive inhibitor of the human ADAM10 catalytic/disintegrin domain, with a Ki of 48nM. Moreover, 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.


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