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Degradome of soluble ADAM10 and ADAM17 metalloproteases

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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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MS data

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [95] partner repository with the data set identifier PXD013718.

Abbreviations

ACN:

Acetonitrile

ADAM:

A disintegrin and metalloprotease

APP:

Amyloid precursor protein

CTF:

C-terminal fragment

DAPT:

N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester

DCM:

Dilated cardiomyopathy

dnp:

2,4-Dinitrophenyl

ECM:

Extracellular matrix

FCS:

Fetal calf serum

HEK:

Human embryonic kidney

LC–MS/MS:

Liquid chromatography–tandem mass spectrometry

Mca:

7-Methyloxycoumarin-4-yl-acetyl

MMP:

Matrix metalloproteinase

PCPE-1:

Procollagen C-proteinase enhancer-1

PSM:

Peptide scoring matches

RFU:

Relative fluorescence unit

SD:

Standard deviation

TAILS:

Terminal amine isotopic labeling of substrates

TCA:

Trichloracetic acid

TFA:

Trifluoroacetic acid

TIMP:

Tissue inhibitor of metalloproteinases

TMT:

Tandem mass tag

TR:

Technical replicate

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Acknowledgements

We thank William C. Claycomb (Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana) for providing HL-1 cells. We thank Björn Rabe from the Biochemical Institute of the University of Kiel for ADAM10−/−; 17−/− HEK293T cells.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SFB 877 (Proteolysis as a Regulatory Event in Pathophysiology, Projects A1, A9, A15 and Z2), BE 4086/2-2 (C.B.-P.), University of Lyon (C.M.), FOR2290 (S.F.L.), PI379/5-2 (C.U.P.), and BA1606/3-1 (J.W.B).

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Authors and Affiliations

  1. Unit for Degradomics of the Protease Web, Biochemical Institute, University of Kiel, Kiel, Germany

    Franka Scharfenberg, Martin Sammel, Florian Peters, Rielana Wichert, Maximilian Bettendorff & Christoph Becker-Pauly

  2. Systematic Proteomics and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel, Germany

    Andreas Helbig & Andreas Tholey

  3. Department of Neurosurgery, Philipps University Marburg, Marburg, Germany

    Julia Benzel, Uwe Schlomann & Jörg W. Bartsch

  4. Biochemical Institute, University of Kiel, Kiel, Germany

    Dirk Schmidt-Arras & Stefan Rose-John

  5. Tissue Biology and Therapeutic Engineering Unit, LBTI, UMR 5305, Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, 69367, Lyon, France

    Catherine Moali

  6. Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Institute for Advanced Study, Technical University Munich, Munich, Germany

    Stefan F. Lichtenthaler

  7. Munich Center for Systems Neurology (SyNergy), Munich, Germany

    Stefan F. Lichtenthaler

  8. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Stefan F. Lichtenthaler

  9. Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Claus U. Pietrzik

Authors
  1. Franka Scharfenberg
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  2. Andreas Helbig
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  3. Martin Sammel
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  4. Julia Benzel
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  15. Andreas Tholey
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Contributions

Conceptualization, FS and CB-P; methodology, investigation, and data analysis, FS, AH, MS, JB, US, FP, RW, MB, DS-A, SR-J, CM, SFL, CUP, JWB, AT, and CB-P; writing, FS and CB-P.

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Correspondence to Franka Scharfenberg or Christoph Becker-Pauly.

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Scharfenberg, F., Helbig, A., Sammel, M. et al. Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cell. Mol. Life Sci. 77, 331–350 (2020). https://doi.org/10.1007/s00018-019-03184-4

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