title: Phosphatidylserine exposure is required for ADAM17 sheddase function.
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.
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
authors.forename: Anselm
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kordowski
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
authors.forename: Joscha
authors.initials: J
authors.lastname: Büch
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Evers
authors.affiliation: Hamburg University of Applied Science, Ulmenliet 20, Hamburg 21033, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Andrä
authors.affiliation: Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Düsterhöft
authors.affiliation: Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Michalek
authors.affiliation: Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, Germany.
authors.forename: Inken
authors.initials: I
authors.lastname: Lorenzen
authors.affiliation: Division of Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel 24105, Germany.
authors.forename: Prasath
authors.initials: P
authors.lastname: Somasundaram
authors.affiliation: Division of Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel 24105, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tholey
authors.affiliation: Otto Diels Institute for Organic Chemistry, University of Kiel, Kiel 24118, Germany.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sönnichsen
authors.affiliation: Physiological Institute, University of Regensburg, Universitätsstrasse 31, Regensburg 93053, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
authors.affiliation: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.affiliation: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Nehls
authors.affiliation: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.affiliation: Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
authors.forename: Sucharit
authors.initials: S
authors.lastname: Bhakdi
authors.affiliation: Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany.
authors.forename: Karina
authors.initials: K
authors.lastname: Reiss
mesh_terms: D000072198:ADAM17 Protein / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000097:blood / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008555:Melitten / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010718:Phosphatidylserines / Q000378:metabolism*; D000072417:Protein Domains; D013379:Substrate Specificity
chemical_list: D010718:Phosphatidylserines; D008555:Melitten; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse