Sommer, Anselm and Kordowski, Felix and Buech, Joscha and Maretzky, Thorsten and Evers, Astrid and Andrae, Joerg and Duesterhoeft, Stefan and Michalek, Matthias and Lorenzen, Inken and Somasundaram, Prasath and Tholey, Andreas and Soennichsen, Frank D. and Kunzelmann, Karl and Heinbockel, Lena and Nehls, Christian and Gutsmann, Thomas and Groetzinger, Joachim and Bhakdi, Sucharit and Reiss, Karina (2016) Phosphatidylserine exposure is required for ADAM17 sheddase function. NATURE COMMUNICATIONS, 7: 11523. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NECROSIS-FACTOR-ALPHA; CONVERTING-ENZYME; L-SELECTIN; SUBSTRATE SELECTIVITY; SHEDDING ACTIVITY; APOPTOTIC CELLS; BLOOD-CELLS; ECTODOMAIN; ACTIVATION; RECEPTOR; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Mar 2019 15:09 |
| Last Modified: | 25 Mar 2019 15:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3029 |
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