| Literature DB >> 31160781 |
Yongchan Lee1,2, Pattama Wiriyasermkul3, Chunhuan Jin4, Lili Quan4, Ryuichi Ohgaki4, Suguru Okuda4, Tsukasa Kusakizako1, Tomohiro Nishizawa1, Kazumasa Oda1, Ryuichiro Ishitani1,5, Takeshi Yokoyama6, Takanori Nakane1,7, Mikako Shirouzu6, Hitoshi Endou8, Shushi Nagamori3,9, Yoshikatsu Kanai4, Osamu Nureki10.
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.Entities:
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Year: 2019 PMID： 31160781 DOI： 10.1038/s41594-019-0237-7
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 15.369