Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.
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:
06 2019
06 2019
Historique:
received:
03
03
2019
accepted:
26
04
2019
pubmed:
5
6
2019
medline:
20
2
2020
entrez:
5
6
2019
Statut:
ppublish
Résumé
The L-type amino acid transporter 1 (LAT1 or SLC7A5) transports large neutral amino acids across the membrane and is crucial for brain drug delivery and tumor growth. LAT1 forms a disulfide-linked heterodimer with CD98 heavy chain (CD98hc, 4F2hc or SLC3A2), but the mechanism of assembly and amino acid transport are poorly understood. Here we report the cryo-EM structure of the human LAT1-CD98hc heterodimer at 3.3-Å resolution. LAT1 features a canonical Leu T-fold and exhibits an unusual loop structure on transmembrane helix 6, creating an extended cavity that might accommodate bulky amino acids and drugs. CD98hc engages with LAT1 through the extracellular, transmembrane and putative cholesterol-mediated interactions. We also show that two anti-CD98 antibodies recognize distinct, multiple epitopes on CD98hc but not its glycans, explaining their robust reactivities. These results reveal the principles of glycoprotein-solute carrier assembly and provide templates for improving preclinical drugs and antibodies targeting LAT1 or CD98hc.
Identifiants
pubmed: 31160781
doi: 10.1038/s41594-019-0237-7
pii: 10.1038/s41594-019-0237-7
doi:
Substances chimiques
Fusion Regulatory Protein 1, Heavy Chain
0
Large Neutral Amino Acid-Transporter 1
0
SLC3A2 protein, human
0
SLC7A5 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
510-517Références
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