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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.

Author information

1
Unit for Degradomics of the Protease Web, Biochemical Institute, University of Kiel, Kiel, Germany. fscharfenberg@biochem.uni-kiel.de.
2
Systematic Proteomics and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel, Germany.
3
Unit for Degradomics of the Protease Web, Biochemical Institute, University of Kiel, Kiel, Germany.
4
Department of Neurosurgery, Philipps University Marburg, Marburg, Germany.
5
Biochemical Institute, University of Kiel, Kiel, Germany.
6
Tissue Biology and Therapeutic Engineering Unit, LBTI, UMR 5305, Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, 69367, Lyon, France.
7
Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Institute for Advanced Study, Technical University Munich, Munich, Germany.
8
Munich Center for Systems Neurology (SyNergy), Munich, Germany.
9
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
10
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
11
Unit for Degradomics of the Protease Web, Biochemical Institute, University of Kiel, Kiel, Germany. cbeckerpauly@biochem.uni-kiel.de.

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.

KEYWORDS:

ADAM10; ADAM17; ADAM8; Ectodomain shedding; Proteolysis; TAILS

PMID:
31209506
DOI:
10.1007/s00018-019-03184-4

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