Cell biology

Cystine

Antiporter

Amino acid

Biology

Receptor

Biochemistry

Glutathione

Cysteine

Intracellular

Ligand (biochemistry)

Membrane

Enzyme

Glutamate receptor

Tripeptide

Allosteric regulation

Chemistry

Biophysics

Nature Communications

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.

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