Mutagenesis of the ADAM17-phosphatidylserine-binding motif leads to embryonic lethality in mice.
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
15
05
2019
revised:
19
08
2019
accepted:
19
08
2019
entrez:
29
8
2019
pubmed:
29
8
2019
medline:
1
7
2020
Statut:
epublish
Résumé
ADAM17, prominent member of the "Disintegrin and Metalloproteinase" (ADAM) family, controls vital cellular functions through cleavage of transmembrane substrates. Several of these play central roles in oncogenesis and inflammation, yet despite its importance, the mechanism by which ADAM17 is activated is not fully understood. We recently presented evidence that surface exposure of phosphatidylserine (PS) is the penultimate event required for sheddase activation, which occurs upon binding of a membrane-proximal, cationic binding motif to the anionic phospholipid headgroup. Here, we show that mutagenesis of the 3 amino acids constituting the PS-binding motif leads to embryonic lethality in mice. Heterozygotes showed no abnormalities. Primary hepatocytes and fibroblasts were analysed and found to express the mutant protease on the cell surface. However, PMA-stimulated release of ADAM17 substrates was completely abolished. The results directly support the novel concept of transiently externalised PS as essential trigger of extracellular protease function in vivo.
Identifiants
pubmed: 31455669
pii: 2/5/e201900430
doi: 10.26508/lsa.201900430
pmc: PMC6712283
pii:
doi:
Substances chimiques
Phosphatidylserines
0
phorbolol myristate acetate
56937-68-9
ADAM17 Protein
EC 3.4.24.86
Adam17 protein, mouse
EC 3.4.24.86
Tetradecanoylphorbol Acetate
NI40JAQ945
Banques de données
GENBANK
['NM_009615.6']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 Veit et al.
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