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Molecular basis for redox control by the human cystine/glutamate antiporter system xc−

Author

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  • Joanne L. Parker

    (University of Oxford)

  • Justin C. Deme

    (University of Oxford
    University of Oxford
    National Cancer Institute)

  • Dimitrios Kolokouris

    (University of Oxford)

  • Gabriel Kuteyi

    (University of Oxford)

  • Philip C. Biggin

    (University of Oxford)

  • Susan M. Lea

    (University of Oxford
    University of Oxford
    National Cancer Institute)

  • Simon Newstead

    (University of Oxford
    University of Oxford)

Abstract

Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of cysteine. However, circulating cysteine exists in the blood as the oxidised di-peptide cystine, requiring specialised transport systems for its import into the cell. System xc− is a dedicated cystine transporter, importing cystine in exchange for intracellular glutamate. To counteract elevated levels of reactive oxygen species in cancerous cells system xc− is frequently upregulated, making it an attractive target for anticancer therapies. However, the molecular basis for ligand recognition remains elusive, hampering efforts to specifically target this transport system. Here we present the cryo-EM structure of system xc− in both the apo and glutamate bound states. Structural comparisons reveal an allosteric mechanism for ligand discrimination, supported by molecular dynamics and cell-based assays, establishing a mechanism for cystine transport in human cells.

Suggested Citation

  • Joanne L. Parker & Justin C. Deme & Dimitrios Kolokouris & Gabriel Kuteyi & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Molecular basis for redox control by the human cystine/glutamate antiporter system xc−," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27414-1
    DOI: 10.1038/s41467-021-27414-1
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    References listed on IDEAS

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    1. Josep Rullo-Tubau & Maria Martinez-Molledo & Paola Bartoccioni & Ignasi Puch-Giner & Ángela Arias & Suwipa Saen-Oon & Camille Stephan-Otto Attolini & Rafael Artuch & Lucía Díaz & Víctor Guallar & Ekai, 2024. "Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. 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.

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