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

  • Nat Commun. 2021 Dec 8;12(1):7147. doi: 10.1038/s41467-021-27414-1.
Joanne L Parker  #  1 ,  Justin C Deme  #  2  3  4 ,  Dimitrios Kolokouris  5 ,  Gabriel Kuteyi  5 ,  Philip C Biggin  5 ,  Susan M Lea  6  7  8 ,  Simon Newstead  9  10
Affiliations
  • 1. Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. [email protected].
  • 2. Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
  • 3. Central Oxford Structural Molecular Imaging Centre, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
  • 4. Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA.
  • 5. Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
  • 6. Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK. [email protected].
  • 7. Central Oxford Structural Molecular Imaging Centre, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK. [email protected].
  • 8. Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA. [email protected].
  • 9. Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK. [email protected].
  • 10. The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK. [email protected].
  • # Contributed equally.
PMID: 34880232 DOI: 10.1038/s41467-021-27414-1
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.