6JMQ

LAT1-CD98hc complex bound to MEM-108 Fab

Summary for 6JMQ

• Entry DOI: 10.2210/pdb6jmq/pdb
• EMDB information: 9849
• Descriptor: Large neutral amino acids transporter small subunit 1, 4F2 cell-surface antigen heavy chain, Antibody, ... (7 entities in total)
• Functional Keywords: transporter, glycoprotein, complex, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 172939.68

Authors

Lee, Y.,Nishizawa, T.,Kusakizako, T.,Oda, K.,Ishitani, R.,Nakane, T.,Nureki, O. (deposition date: 2019-03-13, release date: 2019-06-19, Last modification date: 2024-10-30)

Primary citation

Lee, Y.,Wiriyasermkul, P.,Jin, C.,Quan, L.,Ohgaki, R.,Okuda, S.,Kusakizako, T.,Nishizawa, T.,Oda, K.,Ishitani, R.,Yokoyama, T.,Nakane, T.,Shirouzu, M.,Endou, H.,Nagamori, S.,Kanai, Y.,Nureki, O.
Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc.
Nat.Struct.Mol.Biol., 26:510-517, 2019

PubMed 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.

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

Experimental method

ELECTRON MICROSCOPY (3.31 Å)