Physics Department, Shahid Beheshti University, G.C., Evin, Tehran, 19839, Iran; Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
Research Group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
Arch Biochem Biophys. 2019 Mar 30;664:117-126. doi: 10.1016/j.abb.2019.01.039. Epub 2019 Feb 6.
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 Cys 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.
细胞外胱氨酸 (CYC) 通过 xC 反向转运体摄取对细胞活力很重要。特别是在癌细胞中，观察到 xC 活性上调，这可以保护这些细胞免受细胞内氧化应激。因此，抑制 CYC 的摄取最终可能导致癌细胞死亡。到目前为止，xC 反向转运体摄取 CYC 的分子水平机制尚未详细研究。在这项研究中，我们应用了几种不同的模拟技术来研究 CYC 通过 xC 反向转运体的转运，xCT 是 xC 反向转运体的轻亚基，负责 CYC 和谷氨酸的转运。具体来说，我们研究了 CYC 在三种模型系统中的渗透，即 xCT 的向外（OF）、封闭（OCC）和向内（IF）构象。我们还研究了突变 Cys 为 Ala 对 xCT 的影响，这在文献中也进行了实验研究。这使我们能够将计算结果与实验观察结果进行定性比较，从而验证我们的模拟。总之，我们的模拟提供了 CYC 通过 xC 反向转运体转运的分子水平机制，更具体地说，xCT 中的哪些氨基酸残基在 CYC 的摄取、转运和释放中起关键作用。
