ADAM10 sheddase activation is controlled by cell membrane asymmetry
| Autor: | Jörg Andrä, Björn Rabe, Karl Kunzelmann, Anselm Sommer, Florian Bleibaum, Karina Reiss, Martin Veit, Christian Nehls, Sucharit Bhakdi, Wilmar Correa, Joachim Grötzinger, Thomas Gutsmann |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
phosphatidylserine Phospholipid scramblase Erythrocytes ADAM10 Anoctamins Models Biological cell membrane asymmetry Cell Line Cell membrane 03 medical and health sciences chemistry.chemical_compound shedding ADAM10 Protein Phosphoserine Structure-Activity Relationship 0302 clinical medicine Scott syndrome Chlorocebus aethiops Genetics medicine Extracellular Animals Humans Amino Acid Sequence Molecular Biology Chemistry Anoctamin-6 Cell Membrane Membrane Proteins Cell Biology General Medicine Transfection Phosphatidylserine Sheddase medicine.disease Cell biology Enzyme Activation 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis COS Cells Original Article activation Rabbits Biomarkers |
| Zdroj: | Journal of Molecular Cell Biology |
| ISSN: | 1759-4685 1674-2788 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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