Degradome of soluble ADAM10 and ADAM17 metalloproteases

Disintegrin and metalloproteinases (ADAMs) 10 and 17 can release the extracellular part of a variety of membrane-bound proteins via ectodomain shedding important for many biological functions. So far, substrate identification focused exclusively on membrane-anchored ADAM10 and ADAM17. However, besid...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2020-01, Vol.77 (2), p.331-350
Main Authors: Scharfenberg, Franka, Helbig, Andreas, Sammel, Martin, Benzel, Julia, Schlomann, Uwe, Peters, Florian, Wichert, Rielana, Bettendorff, Maximilian, Schmidt-Arras, Dirk, Rose-John, Stefan, Moali, Catherine, Lichtenthaler, Stefan F., Pietrzik, Claus U., Bartsch, Jörg W., Tholey, Andreas, Becker-Pauly, Christoph
Format: Article
Language:English
Subjects:
ADAM10 Protein - metabolism
ADAM17 Protein - metabolism
ADAM8 protein
Amino acids
Amino Acids - metabolism
Amyloid Precursor Protein Secretases - metabolism
Animals
Biochemistry
Biochemistry, Molecular Biology
Biomedical and Life Sciences
Biomedicine
Cadherins
Cardiomyocytes
Cell Behavior
Cell Biology
Cell Line
Cellular Biology
Cleavage
Cystatin C
Fibronectin
Genomics
HEK293 Cells
Humans
Life Sciences
Mass spectrometry
Mass spectroscopy
Membrane Proteins - metabolism
Metalloproteases - metabolism
Mice
Myocytes, Cardiac - metabolism
Original
Original Article
Protease
Proteinase
Proteins
Proteolysis
Secretome
Shedding
Subcellular Processes
Substrates
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Summary:Disintegrin and metalloproteinases (ADAMs) 10 and 17 can release the extracellular part of a variety of membrane-bound proteins via ectodomain shedding important for many biological functions. So far, substrate identification focused exclusively on membrane-anchored ADAM10 and ADAM17. However, besides known shedding of ADAM10, we identified ADAM8 as a protease capable of releasing the ADAM17 ectodomain. Therefore, we investigated whether the soluble ectodomains of ADAM10/17 (sADAM10/17) exhibit an altered substrate spectrum compared to their membrane-bound counterparts. A mass spectrometry-based N-terminomics approach identified 134 protein cleavage events in total and 45 common substrates for sADAM10/17 within the secretome of murine cardiomyocytes. Analysis of these cleavage sites confirmed previously identified amino acid preferences. Further in vitro studies verified fibronectin, cystatin C, sN-cadherin, PCPE-1 as well as sAPP as direct substrates of sADAM10 and/or sADAM17. Overall, we present the first degradome study for sADAM10/17, thereby introducing a new mode of proteolytic activity within the protease web.
ISSN:1420-682X
1420-9071
DOI:10.1007/s00018-019-03184-4