Molecular basis for redox control by the human cystine/glutamate antiporter System xc -
Molecular basis for redox control by the human cystine/glutamate antiporter System xc -
复制标题
人胱氨酸/谷氨酸逆向转运蛋白系统 xc 氧化还原控制的分子基础 -
DOI：
10.1101/2021.08.09.455631
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Parker J
中科院分区：
文献类型：
--
作者：
Parker J
半胱氨酸作为谷胱甘肽(GSH)三肽的关键成分，在细胞氧化还原平衡中起着至关重要的作用。细胞GSH合成的一个限速步骤是半胱氨酸的可获得性。然而，循环中的半胱氨酸以氧化的二肽半胱氨酸的形式存在于血液中，需要特殊的运输系统才能将其输入细胞。System XC−是一种专用的胱氨酸转运体，通过进口胱氨酸来换取细胞内的谷氨酸。为了抵消癌细胞系统中活性氧物种水平的升高，XC−经常上调，使其成为抗癌治疗的有吸引力的靶点。然而，配体识别的分子基础仍然难以捉摸，阻碍了专门针对这一运输系统的努力。在这里，我们介绍了XC-−体系在载脂蛋白和谷氨酸结合状态下的低温EM结构。结构比较揭示了配体识别的变构机制，并得到了分子动力学和基于细胞的分析的支持，从而建立了胱氨酸在人类细胞中的运输机制。
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.