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Nat Commun. 2016 May 10;7:11523. doi: 10.1038/ncomms11523.

Phosphatidylserine exposure is required for ADAM17 sheddase function.

Author information

1
Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
2
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021, USA.
3
Hamburg University of Applied Science, Ulmenliet 20, Hamburg 21033, Germany.
4
Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, Germany.
5
Division of Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel 24105, Germany.
6
Otto Diels Institute for Organic Chemistry, University of Kiel, Kiel 24118, Germany.
7
Physiological Institute, University of Regensburg, Universitätsstrasse 31, Regensburg 93053, Germany.
8
Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, Germany.

Abstract

ADAM17, a prominent member of the 'Disintegrin and Metalloproteinase' (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Here we present evidence that surface exposure of phosphatidylserine (PS) is pivotal for ADAM17 to exert sheddase activity. PS exposure is tightly coupled to substrate shedding provoked by diverse ADAM17 activators. PS dependency is demonstrated in the following: (a) in Raji cells undergoing apoptosis; (b) in mutant PSA-3 cells with manipulatable PS content; and (c) in Scott syndrome lymphocytes genetically defunct in their capacity to externalize PS in response to intracellular Ca(2+) elevation. Soluble phosphorylserine but not phosphorylcholine inhibits substrate cleavage. The isolated membrane proximal domain (MPD) of ADAM17 binds to PS but not to phosphatidylcholine liposomes. A cationic PS-binding motif is identified in this domain, replacement of which abrogates liposome-binding and renders the protease incapable of cleaving its substrates in cells. We speculate that surface-exposed PS directs the protease to its targets where it then executes its shedding function.

PMID:
27161080
PMCID:
PMC4866515
DOI:
10.1038/ncomms11523
[Indexed for MEDLINE]
Free PMC Article

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