Meprin is a zinc endopeptidase of the astacin family, which is expressed as a membrane-bound or secreted protein in mammalian epithelial cells, in intestinal leucocytes and in certain cancer cells. There are two types of meprin subunits, α and β, which form disulphide-bonded homo- and hetero-oligomers. Here we report on the cleavage of matrix proteins by hmeprin (human meprin) α and β homo-oligomers, and on the interactions of these enzymes with inhibitors. Despite their completely different cleavage specificities, both hmeprin α and β are able to hydrolyse basement membrane components such as collagen IV, nidogen-1 and fibronectin. However, they are inactive against intact collagen I. Hence the matrix-cleaving activity of hmeprin resembles that of gelatinases rather than collagenases. Hmeprin is inhibited by hydroxamic acid derivatives such as batimastat, galardin and Pro-Leu-Gly-hydroxamate, by TAPI-0 (tumour necrosis factor α protease inhibitor-0) and TAPI-2, and by thiol-based compounds such as captopril. Therapeutic targets for these inhibitors are MMPs (matrix metalloproteases), TACE (tumour necrosis factor α-converting enzyme) and angiotensin-converting enzyme respectively. The most effective inhibitor of hmeprin α in the present study was the naturally occurring hydroxamate actinonin (Ki=20 nM). The marked variance in the cleavage specificities of hmeprin α and β is reflected by their interaction with the TACE inhibitor Ro 32-7315, whose affinity for the β subunit (IC50=1.6 mM) is weaker by three orders of magnitude than that for the α subunit (Ki=1.6 µM). MMP inhibitors such as the pyrimidine-2,4,6-trione derivative Ro 28-2653 that are more specific for gelatinases do not bind to hmeprin, presumably due to the subtle differences in the mode of zinc binding and active-site structure between the astacins and the MMPs.
Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors
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Markus-N. KRUSE, Christoph BECKER, Daniel LOTTAZ, Danny KÖHLER, Irene YIALLOUROS, Hans-Willi KRELL, Erwin E. STERCHI, Walter STÖCKER; Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J 1 March 2004; 378 (2): 383–389. doi: https://doi.org/10.1042/bj20031163
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