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Structure paper

TitleCryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.
Journal, issue, pagesNat Struct Mol Biol, Vol. 26, Issue 6, Page 510-517, Year 2019
Publish dateJun 3, 2019
AuthorsYongchan Lee / Pattama Wiriyasermkul / Chunhuan Jin / Lili Quan / Ryuichi Ohgaki / Suguru Okuda / Tsukasa Kusakizako / Tomohiro Nishizawa / Kazumasa Oda / Ryuichiro Ishitani / Takeshi Yokoyama / Takanori Nakane / Mikako Shirouzu / Hitoshi Endou / Shushi Nagamori / Yoshikatsu Kanai / Osamu Nureki /
PubMed AbstractThe 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 ...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.
External linksNat Struct Mol Biol / PubMed:31160781
MethodsEM (single particle)
Resolution3.31 - 4.1 Å
Structure data

EMDB-9849, PDB-6jmq:
LAT1-CD98hc complex bound to MEM-108 Fab
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-9850, PDB-6jmr:
CD98hc extracellular domain bound to HBJ127 Fab and MEM-108 Fab
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / Transporter / Glycoprotein / Complex / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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