Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex
Abstract
The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner 1-3 . LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes 2-6 . Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs 7-11 . LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane 8,9 . Despite extensive cell-based characterization of the LAT1-4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown 12-19 . Here we report the cryo-electron microscopy structures of human LAT1-4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential fo…
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Co-immunoprecipitation of Slc7a5 from neural cells confirmed its interaction with Slc3a2 and excluded interactions with components of the B1/B3 integrin pathway.
“Indeed, a co-immunoprecipitation experiment of Slc7a5 from neural cells, while confirming its interaction with Slc3a2, 34 excluded interactions with components of the B1/ B3 integrin pathway (Data S6).”
From Large neutral amino acid levels tune perinatal neuronal excitability and survival (2023) · cites this paper as [34]
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References 38 · Cited by 358
- Authors
- Yan, R., Zhao, X., Lei, J., & Zhou, Q.
- Affiliations
- Center for Life Sciences (CN)
- Tsinghua University (CN)
- Westlake University (CN)
- Corresponding author
- Zhou, Qiang
- Venue
- Nature
- Published
- 2019-03-13
- Volume
- 568
- Issue
- 7750
- Pages
- 127-130
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2922210770
- Cited by
- 358
- References
- 38
- Citations by year
- 2026: 32 · 2025: 47 · 2024: 78 · 2023: 36 · 2022: 50 · 2021: 46 · 2020: 45 · 2019: 24
- FWCI
- 17.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Tsinghua University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- LAT1, SLC7A5, 4F2hc, SLC3A2, L-type amino acid transporter, antiporters, inhibitor complex, transporter conformation, disulfide bonds, membrane protein structure, anticancer drug targets
- MeSH terms
- Amino Acids, Binding Sites, Biological Transport, Carboxylic Acids, Disulfides, Humans, Models, Molecular, Norbornanes, Protein Binding, Protein Conformation, Cryoelectron Microscopy, Fusion Regulatory Protein 1, Heavy Chain, Large Neutral Amino Acid-Transporter 1, Multiprotein Complexes
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