The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10
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Publication Details
Output type: Journal article
Author list: Jefferson T., Auf Dem Keller U., Bellac C., Metz V., Broder C., Hedrich J., Ohler A., Maier W., Magdolen V., Sterchi E., Bond J., Jayakumar A., Traupe H., Chalaris A., Rose-John S., Pietrzik C., Postina R., Overall C., Becker-Pauly C.
Publisher: Springer
Publication year: 2013
Journal: Cellular and Molecular Life Sciences (1420-682X)
Volume number: 70
Issue number: 2
Start page: 309
End page: 333
Number of pages: 25
ISSN: 1420-682X
eISSN: 1420-9071
URL: http://api.elsevier.com/content/abstract/scopus_id:84872325609
Unpaywall Data
Open access status: hybrid
Full text URL: https://link.springer.com/content/pdf/10.1007/s00018-012-1106-2.pdf
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. © 2012 The Author(s).
Keywords
ADAM10, Degradome, Meprin, Metalloproteases, Proteomics, TAILS
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