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Degradome of soluble ADAM10 and ADAM17 metalloproteases.

Cell Mol Life Sci. 2019 Jun 17. doi: 10.1007/s00018-019-03184-4. [Epub ahead of print]

Authors/Editors: Scharfenberg F, Helbig A, Sammel M, Benzel J, Schlomann U, Peters F, Wichert R, Bettendorff M, Schmidt-Arras D, Rose-John S, Moali C, Lichtenthaler SF, Pietrzik CU, Bartsch JW, Tholey A, Becker-Pauly C.
Publication Date: 2019

08_scharfenberg

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.

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