Journal article
Phosphatidylserine exposure is required for ADAM17 sheddase function
Nature communications, Vol.7(1), pp.11523-11523
05/10/2016
DOI: 10.1038/ncomms11523
PMCID: PMC4866515
PMID: 27161080
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.
Details
- Title: Subtitle
- Phosphatidylserine exposure is required for ADAM17 sheddase function
- Creators
- Anselm Sommer - Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, GermanyFelix Kordowski - Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, GermanyJoscha Büch - Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, GermanyThorsten Maretzky - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021, USAAstrid Evers - Arthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York 10021, USAJörg Andrä - Hamburg University of Applied Science, Ulmenliet 20, Hamburg 21033, GermanyStefan Düsterhöft - Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, GermanyMatthias Michalek - Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, GermanyInken Lorenzen - Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, GermanyPrasath Somasundaram - Division of Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel 24105, GermanyAndreas Tholey - Division of Systematic Proteome Research and Bioanalytics, Institute for Experimental Medicine, University of Kiel, Kiel 24105, GermanyFrank D Sönnichsen - Otto Diels Institute for Organic Chemistry, University of Kiel, Kiel 24118, GermanyKarl Kunzelmann - Physiological Institute, University of Regensburg, Universitätsstrasse 31, Regensburg 93053, GermanyLena Heinbockel - Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, GermanyChristian Nehls - Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, GermanyThomas Gutsmann - Forschungszentrum Borstel, Leibniz-Zentrum für Medizin and Biowissenschaften, Borstel 23845, GermanyJoachim Grötzinger - Institute of Biochemistry, University of Kiel, Olshausenstrasse 40, Kiel 24098, GermanySucharit Bhakdi - Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, GermanyKarina Reiss - Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, Kiel 24105, Germany
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.7(1), pp.11523-11523
- DOI
- 10.1038/ncomms11523
- PMID
- 27161080
- PMCID
- PMC4866515
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Language
- English
- Date published
- 05/10/2016
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984094558902771
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