TY - JOUR
T1 - Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc
AU - Lee, Yongchan
AU - Wiriyasermkul, Pattama
AU - Jin, Chunhuan
AU - Quan, Lili
AU - Ohgaki, Ryuichi
AU - Okuda, Suguru
AU - Kusakizako, Tsukasa
AU - Nishizawa, Tomohiro
AU - Oda, Kazumasa
AU - Ishitani, Ryuichiro
AU - Yokoyama, Takeshi
AU - Nakane, Takanori
AU - Shirouzu, Mikako
AU - Endou, Hitoshi
AU - Nagamori, Shushi
AU - Kanai, Yoshikatsu
AU - Nureki, Osamu
N1 - Funding Information:
We thank R. Danev and M. Kikkawa for setting up the cryo-EM infrastructure; K. Ogomori and M. Miyazaki for technical assistance; G. Kasuya, M. Fukuda and R. Taniguchi for discussions; and W. Kühlbrandt for comments on the manuscript. Y.L. was supported by the Toyobo Biotechnology Foundation Fellowship. This work was supported in part by MEXT/JSPS KAKENHI under grant numbers JP16J07405, to Y.L., and JP16H06294, to O.N.; by AMED under grant numbers JP18am0101082, to M.S., JP18gm0810010, to S.N., JP18cm0106131, to Y.K., and JP18am0101115, to O.N.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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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U2 - 10.1038/s41594-019-0237-7
DO - 10.1038/s41594-019-0237-7
M3 - Article
C2 - 31160781
AN - SCOPUS:85066955443
VL - 26
SP - 510
EP - 517
JO - Nature Structural Biology
JF - Nature Structural Biology
SN - 1545-9993
IS - 6
ER -