Bleibaum, Florian and Sommer, Anselm and Veit, Martin and Rabe, Bjoern and Andrae, Joerg and Kunzelmann, Karl and Nehls, Christian and Correa, Wilmar and Gutsmann, Thomas and Groetzinger, Joachim and Bhakdi, Sucharit and Reiss, Karina (2019) ADAM10 sheddase activation is controlled by cell membrane asymmetry. JOURNAL OF MOLECULAR CELL BIOLOGY, 11 (11). pp. 979-993. ISSN 1674-2788, 1759-4685
Full text not available from this repository. (Request a copy)Abstract
Dysregulation of the disintegrin-metalloproteinase ADAM10 may contribute to the development of diseases including tumorigenesis and Alzheimer's disease. The mechanisms underlying ADAM10 sheddase activation are incompletely understood. Here, we show that transient exposure of the negatively charged phospholipid phosphatidylserine (PS) is necessarily required. The soluble PS headgroup was found to act as competitive inhibitor of substrate cleavage. Overexpression of the Ca2+- dependent phospholipid scramblase Anoctamin-6 (ANO6) led to increased PS externalization and substrate release. Transfection with a constitutively active form of ANO6 resulted in maximum sheddase activity in the absence of any stimulus. Calcium-dependent ADAM10 activation could not be induced in lymphocytes of patients with Scott syndrome harbouring a missense mutation in ANO6. A putative PS-binding motif was identified in the conserved stalk region. Replacement of this motif resulted in strong reduction of sheddase activity. In conjunction with the recently described 3D structure of the ADAM10 extracellular domain, a model is advanced to explain how surface-exposed PS triggers ADAM10 sheddase function.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PHOSPHATIDYLSERINE EXPOSURE; L-SELECTIN; RECEPTOR; DISINTEGRIN; ADHESION; ROLES; ALPHA; CD23; PROTEOLYSIS; ENDOTOXINS; ADAM10; activation; shedding; Anoctamin-6; phosphatidylserine; cell membrane asymmetry |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2020 13:02 |
| Last Modified: | 24 Mar 2020 13:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25883 |
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