ADAM10 sheddase activation is controlled by cell membrane asymmetry.
ADAM10 Protein
/ chemistry
Amino Acid Sequence
Animals
Anoctamins
/ metabolism
Biomarkers
COS Cells
Cell Line
Cell Membrane
/ metabolism
Chlorocebus aethiops
Enzyme Activation
Erythrocytes
/ metabolism
Humans
Membrane Proteins
/ metabolism
Models, Biological
Phosphoserine
/ metabolism
Rabbits
Structure-Activity Relationship
ADAM10
Anoctamin-6
activation
cell membrane asymmetry
phosphatidylserine
shedding
Journal
Journal of molecular cell biology
ISSN: 1759-4685
Titre abrégé: J Mol Cell Biol
Pays: United States
ID NLM: 101503669
Informations de publication
Date de publication:
23 12 2019
23 12 2019
Historique:
received:
08
06
2018
revised:
20
11
2018
accepted:
06
02
2019
pubmed:
13
2
2019
medline:
17
7
2020
entrez:
13
2
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30753537
pii: 5316298
doi: 10.1093/jmcb/mjz008
pmc: PMC6927242
doi:
Substances chimiques
Anoctamins
0
Biomarkers
0
Membrane Proteins
0
Phosphoserine
17885-08-4
ADAM10 Protein
EC 3.4.24.81
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
979-993Informations de copyright
© The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.
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