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Originally published In Press as doi:10.1074/jbc.M011414200 on January 22, 2001

J. Biol. Chem., Vol. 276, Issue 16, 13248-13255, April 20, 2001
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Marked Differences between Metalloproteases Meprin A and B in Substrate and Peptide Bond Specificity*

Greg P. BertenshawDagger , Benjamin E. Turk§, Simon J. Hubbard||, Gail L. MattersDagger , John E. BylanderDagger , Jacqueline M. CrismanDagger , Lewis C. Cantley§, and Judith S. BondDagger **

From the Dagger  Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, the § Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, the  Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02215, and the || Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester M60 1QD, United Kingdom

Meprin A and B are highly regulated, secreted, and cell-surface metalloendopeptidases that are abundantly expressed in the kidney and intestine. Meprin oligomers consist of evolutionarily related alpha  and/or beta  subunits. The work herein was carried out to identify bioactive peptides and proteins that are susceptible to hydrolysis by mouse meprins and kinetically characterize the hydrolysis. Gastrin-releasing peptide fragment 14-27 and gastrin 17, regulatory molecules of the gastrointestinal tract, were found to be the best peptide substrates for meprin A and B, respectively. Peptide libraries and a variety of naturally occurring peptides revealed that the meprin beta  subunit has a clear preference for acidic amino acids in the P1 and P1' sites of substrates. The meprin alpha  subunit selected for small (e.g. serine, alanine) or hydrophobic (e.g. phenylalanine) residues in the P1 and P1' sites, and proline was the most preferred amino acid at the P2' position. Thus, although the meprin alpha  and beta  subunits share 55% amino acid identity within the protease domain and are normally localized at the same tissue cell surfaces, they have very different substrate and peptide bond specificities indicating different functions. Homology models of the mouse meprin alpha  and beta  protease domains, based on the astacin crystal structure, revealed active site differences that can account for the marked differences in substrate specificity of the two subunits.

* This work was supported by the American Heart Association Predoctoral Fellowship 9910075U (to G. P. B.), by Department of Defense Grant DAMD17-98-1-8143 (to G. L. M.), and by National Institutes of Health Grants DK19691 and DK54625 (to J. S. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, H171, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850. Tel.: 717-531-8586; Fax: 717-531-7072; E-mail: jbond@psu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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