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

• Published in: Nature communications Vol. 12; no. 1; p. 7147
• Main Authors: Parker, Joanne L., Deme, Justin C., Kolokouris, Dimitrios, Kuteyi, Gabriel, Biggin, Philip C., Lea, Susan M., Newstead, Simon
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/106; 631/45; 631/535/1258/1259; 631/67; 82/80; 82/83; 96; Allosteric properties; Amino Acid Transport System y+ - chemistry; Amino Acid Transport System y+ - metabolism; Antiporters - chemistry; Antiporters - genetics; Antiporters - metabolism; Biochemistry; Blood circulation; Cryoelectron Microscopy; Cysteine; Cysteine - metabolism; Cystine; Cystine - metabolism; Fusion Regulatory Protein 1, Heavy Chain - chemistry; Fusion Regulatory Protein 1, Heavy Chain - metabolism; Glutamic Acid - metabolism; Glutathione; Glutathione - biosynthesis; HEK293 Cells; Humanities and Social Sciences; Humans; Imports; Intracellular; Ligands; Molecular dynamics; multidisciplinary; Neoplasms; Oxidation-Reduction; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Transportation systems; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27414-1

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. System xc- is a cystine transporter that is expressed in the plasma membrane and imports cystine in exchange for intracellular glutamate. Here, the authors present the cryo-EM structure of human system xc- both in the apo form and the glutamate bound state, and further supported by molecular dynamics and cell-based assays they discuss its cystine transport mechanism.