Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 Apr 2024
06 Apr 2024
Historique:
received:
10
10
2023
accepted:
29
03
2024
medline:
7
4
2024
pubmed:
7
4
2024
entrez:
6
4
2024
Statut:
epublish
Résumé
Recent cryoEM studies elucidated details of the structural basis for the substrate selectivity and translocation of heteromeric amino acid transporters. However, Asc1/CD98hc is the only neutral heteromeric amino acid transporter that can function through facilitated diffusion, and the only one that efficiently transports glycine and D-serine, and thus has a regulatory role in the central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, and molecular dynamics to define human Asc1/CD98hc determinants for substrate specificity and gain insights into the mechanisms that govern substrate translocation by exchange and facilitated diffusion. The cryoEM structure of Asc1/CD98hc is determined at 3.4-3.8 Å resolution, revealing an inward-facing semi-occluded conformation. We find that Ser 246 and Tyr 333 are essential for Asc1/CD98hc substrate selectivity and for the exchange and facilitated diffusion modes of transport. Taken together, these results reveal the structural bases for ligand binding and transport features specific to human Asc1.
Identifiants
pubmed: 38582862
doi: 10.1038/s41467-024-47385-3
pii: 10.1038/s41467-024-47385-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2986Subventions
Organisme : "la Caixa" Foundation (Caixa Foundation)
ID : LCF/PR/HR20/52400017
Informations de copyright
© 2024. The Author(s).
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