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Biochem J. 2013 Mar 1;450(2):253-64. doi: 10.1042/BJ20121751.

The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis.

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1
Institute of Biochemistry, Unit for Degradomics of the Protease Web, University of Kiel, Rudolf-Höber-Str. 1, Kiel 24118, Germany.

Abstract

The metalloproteases meprin α and meprin β exhibit structural and functional features that are unique among all extracellular proteases. Although meprins were discovered more than 30 years ago, their precise substrates and physiological roles have been elusive. Both enzymes were originally found to be highly expressed in kidney and intestine, which focused research on these particular tissues and associated pathologies. Only recently it has become evident that meprins exhibit a much broader expression pattern, implicating functions in angiogenesis, cancer, inflammation, fibrosis and neurodegenerative diseases. Different animal models, as well as proteomics approaches for the identification of protease substrates, have helped to reveal more precise molecular signalling events mediated by meprin activity, such as activation and release of pro-inflammatory cytokines. APP (amyloid precursor protein) is cleaved by meprin β in vivo, reminiscent of the β-secretase BACE1 (β-site APP-cleaving enzyme 1). The subsequent release of Aβ (amyloid β) peptides is thought to be the major cause of the neurodegenerative Alzheimer's disease. On the other hand, ADAM10 (a disintegrin and metalloprotease domain 10), which is the constitutive α-secretase, was shown to be activated by meprin β, which is itself shed from the cell surface by ADAM10. In skin, both meprins are overexpressed in fibrotic tumours, characterized by massive accumulation of fibrillar collagens. Indeed, procollagen III is processed to its mature form by meprin α and meprin β, an essential step in collagen fibril assembly. The recently solved crystal structure of meprin β and the unique cleavage specificity of these proteases identified by proteomics will help to generate specific inhibitors that could be used as therapeutics to target meprins under certain pathological conditions.

PMID:
23410038
PMCID:
PMC3573791
DOI:
10.1042/BJ20121751
[Indexed for MEDLINE]
Free PMC Article
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