Article
The alpha and beta subunits of the metalloprotease meprin are expressed in separate layers of human epidermis, revealing different functions in keratinocyte proliferation and differentiation.
Institute of Zoology, Johannes Gutenberg University, Johannes von Müller-Weg 6, Mainz, Germany.
Journal of Investigative Dermatology (impact factor:
6.31).
06/2007;
127(5):1115-25.
DOI:10.1038/sj.jid.5700675
Source: PubMed
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Citations (0)
- Cited In (12)
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Article: The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10.
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ABSTRACT: The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)-the constitutive α-secretase-is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin(-/-) mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.Cellular and Molecular Life Sciences CMLS 09/2012; · 6.57 Impact Factor -
Article: Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane.
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ABSTRACT: Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace.Proceedings of the National Academy of Sciences 09/2012; 109(40):16131-6. · 9.68 Impact Factor -
Article: The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis.
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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.Biochemical Journal 03/2013; 450(2):253-64. · 4.90 Impact Factor
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Keywords
basal keratinocyte proliferation
brush border membranes
cell migration
cell viability
certain cancer cells
epithelial differentiation
human adult low-calcium high-temperature keratinocytes
human epidermis
human skin
hyperproliferative epidermis
marked shift
meprin alpha
meprin beta
recombinant meprin alpha
separate cell layers
stratum corneum
terminal differentiation
two meprin subunits
uppermost layers
zinc endopeptidase meprin
