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.
Highlights
Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH)
The heavy chain of the transporter, 4F2hc (SLC3A2), which is shared with LAT1 (SLC7A5) and LAT2 (SLC7A8), was resolved in the map, including the disulphide bond between Cys[211] in 4F2hc and Cys[158] in xCT and the four N-glycosylation sites
As reported for LAT1, the single transmembrane helices (TMs) helix in 4F2hc interacts extensively with TM4, predominantly through hydrophobic interactions and ‘knobs into holes’ packing, with additional interactions observed with the C-terminal lateral helix in SLC7A11 (Fig. 1d)
Summary
Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). 1234567890():,; Elevated levels of reactive oxygen species (ROS) play fundamental roles in many aspects of tumour development[1,2] and autoimmune diseases[3]. A key step in GSH synthesis is the availability of cysteine, which together with glutamate and glycine form the constituent parts of the tripeptide[8]. Under redox stress conditions mammalian cells use a specific system to increase cystine uptake to increase GSH synthesis, termed system xc− a dedicated cystine-glutamate antiporter (Fig. 1a)[9], which under normal physiological conditions is predominantly expressed in astrocytes within the brain and macrophages[10,11]. The SLC7 family regulates the flow of amino acids in the body[22,23] and can be divided into two subgroups, the cationic amino acid transporters (CATs, SLC7A1–4 and SLC7A14)[24] and the L-type amino acid transporters, or LATs (SLC7A5-13 and SLC7A15)[25], to which system xc− belongs
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