Structural basis of the acyl-transfer mechanism of human GPAT1.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
15
06
2022
accepted:
31
10
2022
pubmed:
16
12
2022
medline:
24
1
2023
entrez:
15
12
2022
Statut:
ppublish
Résumé
Glycerol-3-phosphate acyltransferase (GPAT)1 is a mitochondrial outer membrane protein that catalyzes the first step of de novo glycerolipid biosynthesis. Hepatic expression of GPAT1 is linked to liver fat accumulation and the severity of nonalcoholic fatty liver diseases. Here we present the cryo-EM structures of human GPAT1 in substrate analog-bound and product-bound states. The structures reveal an N-terminal acyltransferase domain that harbors important catalytic motifs and a tightly associated C-terminal domain that is critical for proper protein folding. Unexpectedly, GPAT1 has no transmembrane regions as previously proposed but instead associates with the membrane via an amphipathic surface patch and an N-terminal loop-helix region that contains a mitochondrial-targeting signal. Combined structural, computational and functional studies uncover a hydrophobic pathway within GPAT1 for lipid trafficking. The results presented herein lay a framework for rational inhibitor development for GPAT1.
Identifiants
pubmed: 36522428
doi: 10.1038/s41594-022-00884-7
pii: 10.1038/s41594-022-00884-7
doi:
Substances chimiques
Glycerol-3-Phosphate O-Acyltransferase
EC 2.3.1.15
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
22-30Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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