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

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 ac...

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Published in:Nature structural & molecular biology Vol. 26; no. 6; pp. 510 - 517
Main Authors: Lee, Yongchan, Wiriyasermkul, Pattama, Jin, Chunhuan, Quan, Lili, Ohgaki, Ryuichi, Okuda, Suguru, Kusakizako, Tsukasa, Nishizawa, Tomohiro, Oda, Kazumasa, Ishitani, Ryuichiro, Yokoyama, Takeshi, Nakane, Takanori, Shirouzu, Mikako, Endou, Hitoshi, Nagamori, Shushi, Kanai, Yoshikatsu, Nureki, Osamu
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.06.2019
Subjects:
Amino acids
Antibodies
Assembly
Brain
Brain tumors
Cholesterol
Cryoelectron Microscopy
Drug delivery
Drug delivery systems
Epitopes
Fusion Regulatory Protein 1, Heavy Chain - chemistry
Fusion Regulatory Protein 1, Heavy Chain - metabolism
Fusion Regulatory Protein 1, Heavy Chain - ultrastructure
Glycoproteins
Humans
Large Neutral Amino Acid-Transporter 1 - chemistry
Large Neutral Amino Acid-Transporter 1 - metabolism
Large Neutral Amino Acid-Transporter 1 - ultrastructure
Models, Molecular
Polysaccharides
Protein Conformation
Protein Folding
Protein Multimerization
ISSN:1545-9993, 1545-9985, 1545-9985
Online Access:Get full text
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Summary: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.
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ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/s41594-019-0237-7