Jefferson, Tamara; Auf dem Keller, Ulrich; Bellac, Caroline; Metz, Verena V.; Broder, Claudia; Hedrich, Jana; Ohler, Anke; Maier, Wladislaw; Magdolen, Viktor; Sterchi, Erwin-Ernst; Bond, Judith S; Jayakumar, Arumugam; Traupe, Heiko; Chalaris, Athena; Rose-John, Stefan; Pietrzik, Claus U.; Postina, Rolf; Overall, Christopher M.; Becker-Pauly, Christoph (2013). The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10. Cellular and molecular life sciences, 70(2), pp. 309-333. Springer 10.1007/s00018-012-1106-2
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine |
UniBE Contributor: |
Sterchi, Erwin-Ernst |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
1420-682X |
Publisher: |
Springer |
Language: |
English |
Submitter: |
Patrizia Catucci |
Date Deposited: |
04 Jul 2014 10:15 |
Last Modified: |
05 Dec 2022 14:29 |
Publisher DOI: |
10.1007/s00018-012-1106-2 |
PubMed ID: |
22940918 |
BORIS DOI: |
10.48350/43256 |
URI: |
https://boris.unibe.ch/id/eprint/43256 |
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