Molecular basis for redox control by the human cystine/glutamate antiporter system xc.
Joanne L ParkerJustin C DemeDimitrios KolokourisGabriel KuteyiPhilip Charles BigginSusan M LeaSimon NewsteadPublished in: Nature communications (2021)
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.
Keyphrases
- molecular dynamics
- fluorescent probe
- reactive oxygen species
- single cell
- living cells
- cell therapy
- induced apoptosis
- endothelial cells
- density functional theory
- small molecule
- high throughput
- signaling pathway
- cell cycle arrest
- staphylococcus aureus
- quality improvement
- gene expression
- endoplasmic reticulum stress
- oxidative stress
- cell death
- single molecule
- pseudomonas aeruginosa