Cell Mol Life Sci. 2019 Jun 17. doi: 10.1007/s00018-019-03184-4. [Epub ahead of print]
Degradome of soluble ADAM10 and ADAM17 metalloproteases.
Scharfenberg F1, Helbig A2, Sammel M3, Benzel J4, Schlomann U4, Peters F3, Wichert R3, Bettendorff M3, Schmidt-Arras D5, Rose-John S5, Moali C6, Lichtenthaler SF7,8,9, Pietrzik CU10, Bartsch JW4, Tholey A2, Becker-Pauly C11.
Abstract
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.
