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

Parker, Joanne L., Deme, Justin C., Kolokouris, Dimitrios, Kuteyi, Gabriel, Biggin, Philip C., Lea, Susan M., Newstead, Simon·2021·Nature Communications
DOI 10.1038/s41467-021-27414-1PMC PMC8654953

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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.

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  • Synthesis of GSH is primarily regulated by system XC-, comprised of SLC3A2 (4F2hc), which acts as a chaperone for membrane localisation and stability of SLC7A11.

    “The synthesis of GSH is primarily regulated by system XC -, comprised of the single-pass transmembrane protein SLC3A2 (4F2hc), which is thought to act as a chaperone for the membrane localisation and stability of the glutamate/cysteine antiporter SLC7A11 [119].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [119]

    The Introduction (page not provided) identifies system xc− as the SLC7A11–SLC3A2 heterodimer and says SLC3A2 is necessary for trafficking it to the plasma membrane. It also links cystine uptake through system xc− to increased GSH synthesis under redox stress, but does not say system xc− primarily regulates GSH synthesis or that SLC3A2 stabilizes SLC7A11. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • System XC - plays a key role in maintaining redox homeostasis inside cells via the uptake of cystine in exchange for glutamate, a key step in the synthesis of GSH required for reactive oxygen species (ROS)-detoxifying enzymes.

    “System XC -plays a key role in maintaining redox homeostasis inside cells via the uptake of cystine in exchange for glutamate, a key step in the synthesis of GSH required for reactive oxygen species (ROS)-detoxifying enzymes [119].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [119]

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Metadata

Authors
Parker, J. L., Deme, J. C., Kolokouris, D., Kuteyi, G., Biggin, P. C., Lea, S. M., & Newstead, S.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-12-08
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-27414-1
PMC
PMC8654953
Cited by
272
References
2
Language
en
Licence
Funders
  • RCUK | Medical Research Council (MR/S021043/1, MR/M011984/1)
  • RCUK | Engineering and Physical Sciences Research Council (EP/T022205/1, EP/R029407/1)
  • Wellcome Trust (209194, 100298, 215519, 219531)

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