Transport of cystine across xC^- antiporter

Extracellular cystine (CYC) uptake by xC^- antiporter is important for the cell viability. Especially in cancer cells, the upregulation of xC^- activity is observed, which protects these cells from intracellular oxidative stress. Hence, inhibition of the CYC uptake may eventually lead to cancer cell death. Up to now, the molecular level mechanism of the CYC uptake by xC^- antiporter has not been studied in detail. In this study, we applied several different simulation techniques to investigate the transport of CYC through xCT, the light subunit of the xC^- antiporter, which is responsible for the CYC and glutamate translocation. Specifically, we studied the permeation of CYC across three model systems, i.e., outward facing (OF), occluded (OCC) and inward facing (IF) configurations of xCT. We also investigated the effect of mutation of Cys₃₂₇ to Ala within xCT, which was also studied experimentally in literature. This allowed us to qualitatively compare our computation results with experimental observations, and thus, to validate our simulations. In summary, our simulations provide a molecular level mechanism of the transport of CYC across the xC^- antiporter, more specifically, which amino acid residues in the xC^- antiporter play a key role in the uptake, transport and release of CYC.