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The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation

Author

Listed:
  • Di Wu

    (University of Oxford
    University of Oxford)

  • Renhong Yan

    (Southern University of Science and Technology)

  • Siyuan Song

    (University of Oxford
    University of Oxford)

  • Andrew K. Swansiger

    (1253 University of Oregon)

  • Yaning Li

    (Tsinghua University)

  • James S. Prell

    (1253 University of Oregon)

  • Qiang Zhou

    (Westlake Institute for Advanced Study; Westlake Laboratory of Life Sciences and Biomedicine)

  • Carol V. Robinson

    (University of Oxford
    University of Oxford)

Abstract

The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc)2. When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.

Suggested Citation

  • Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47948-4
    DOI: 10.1038/s41467-024-47948-4
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    References listed on IDEAS

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    1. Yongchan Lee & Pattama Wiriyasermkul & Pornparn Kongpracha & Satomi Moriyama & Deryck J. Mills & Werner Kühlbrandt & Shushi Nagamori, 2022. "Ca2+-mediated higher-order assembly of heterodimers in amino acid transport system b0,+ biogenesis and cystinuria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Hsin-Yung Yen & Kin Kuan Hoi & Idlir Liko & George Hedger & Michael R. Horrell & Wanling Song & Di Wu & Philipp Heine & Tony Warne & Yang Lee & Byron Carpenter & Andreas Plückthun & Christopher G. Tat, 2018. "PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling," Nature, Nature, vol. 559(7714), pages 423-427, July.
    3. Kallol Gupta & Joseph A. C. Donlan & Jonathan T. S. Hopper & Povilas Uzdavinys & Michael Landreh & Weston B. Struwe & David Drew & Andrew J. Baldwin & Phillip J. Stansfeld & Carol V. Robinson, 2017. "The role of interfacial lipids in stabilizing membrane protein oligomers," Nature, Nature, vol. 541(7637), pages 421-424, January.
    4. Ruth Milkereit & Avinash Persaud & Liviu Vanoaica & Adriano Guetg & Francois Verrey & Daniela Rotin, 2015. "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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