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Nat Struct Mol Biol. 2019 Jun;26(6):510-517. doi: 10.1038/s41594-019-0237-7. Epub 2019 Jun 3.

Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.

Author information

1
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
2
Department of Structural Biology, Max Planck Institute of Biophysics, Frankfurt, Germany.
3
Department of Collaborative Research for Bio-Molecular Dynamics, Nara Medical University, Nara, Japan.
4
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan.
5
Preferred Networks, Inc., Tokyo, Japan.
6
Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Kanagawa, Japan.
7
MRC Laboratory of Molecular Biology, Cambridge, UK.
8
J-Pharma Co., Ltd, Kanagawa, Japan.
9
Global Innovation Center, Shiseido Co., Ltd, Kanagawa, Japan.
10
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan. nureki@bs.s.u-tokyo.ac.jp.

Abstract

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.

PMID:
31160781
DOI:
10.1038/s41594-019-0237-7

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