Activation and substrate specificity of the human P4-ATPase ATP8B1.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 11 2023
18 11 2023
Historique:
received:
12
04
2023
accepted:
23
10
2023
medline:
20
11
2023
pubmed:
19
11
2023
entrez:
18
11
2023
Statut:
epublish
Résumé
Asymmetric distribution of phospholipids in eukaryotic membranes is essential for cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. Here, we present a total of nine cryo-electron microscopy structures of the human flippase ATP8B1-CDC50A complex at 2.4 to 3.1 Å overall resolution, along with functional and computational studies, addressing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as a phosphoinositide binding site. We find that the P4-ATPase transport site is occupied by water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identify and characterize the PI(3,4,5)P
Identifiants
pubmed: 37980352
doi: 10.1038/s41467-023-42828-9
pii: 10.1038/s41467-023-42828-9
pmc: PMC10657443
doi:
Substances chimiques
Adenosine Triphosphatases
EC 3.6.1.-
Phospholipid Transfer Proteins
0
Phospholipids
0
Adenosine Triphosphate
8L70Q75FXE
ATP8B1 protein, human
EC 3.6.1.3.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7492Informations de copyright
© 2023. The Author(s).
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