Phosphatidylserine exposure is required for ADAM17 sheddase function

Anselm Sommer, Felix Kordowski, Joscha Büch, Thorsten Maretzky, Astrid Evers, Jörg Andrä, Stefan Düsterhöft, Matthias Michalek, Inken Lorenzen, Prasath Somasundaram, Andreas Tholey, Frank D. Sönnichsen, Karl Kunzelmann, Lena Heinbockel, Christian Nehls, Thomas Gutsmann, Joachim Grötzinger, Sucharit Bhakdi and Karina Reiss ()
Additional contact information
Anselm Sommer: University of Kiel
Felix Kordowski: University of Kiel
Joscha Büch: University of Kiel
Thorsten Maretzky: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University
Astrid Evers: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University
Jörg Andrä: Hamburg University of Applied Science
Stefan Düsterhöft: Institute of Biochemistry, University of Kiel
Matthias Michalek: Institute of Biochemistry, University of Kiel
Inken Lorenzen: Institute of Biochemistry, University of Kiel
Prasath Somasundaram: Institute for Experimental Medicine, University of Kiel
Andreas Tholey: Institute for Experimental Medicine, University of Kiel
Frank D. Sönnichsen: Otto Diels Institute for Organic Chemistry, University of Kiel
Karl Kunzelmann: Physiological Institute, University of Regensburg
Lena Heinbockel: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften
Christian Nehls: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften
Thomas Gutsmann: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften
Joachim Grötzinger: Institute of Biochemistry, University of Kiel
Sucharit Bhakdi: University of Kiel
Karina Reiss: University of Kiel

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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 Ca2+ 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.

Date: 2016
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DOI: 10.1038/ncomms11523

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