Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 77, Issue 2, Pages 331-350Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-019-03184-4
Keywords
TAILS; ADAM8; ADAM10; ADAM17; Ectodomain shedding; Proteolysis
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB 877, BE 4086/2-2]
- University of Lyon [FOR2290, PI379/5-2, BA1606/3-1]
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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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