National Institute of Biological Sciences, Beijing 102206, China.
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China; National Institute of Biological Sciences, Beijing 102206, China.
Cell Metab. 2024 Sep 3;36(9):2118-2129.e6. doi: 10.1016/j.cmet.2024.07.009. Epub 2024 Aug 6.
Copper (Cu) is a co-factor for several essential metabolic enzymes. Disruption of Cu homeostasis results in genetic diseases such as Wilson's disease. Here, we show that the zinc transporter 1 (ZnT1), known to export zinc (Zn) out of the cell, also mediates Cu entry into cells and is required for Cu-induced cell death, cuproptosis. Structural analysis and functional characterization indicate that Cu and Zn share the same primary binding site, allowing Zn to compete for Cu uptake. Among ZnT members, ZnT1 harbors a unique inter-subunit disulfide bond that stabilizes the outward-open conformations of both protomers to facilitate efficient Cu transport. Specific knockout of the ZnT1 gene in the intestinal epithelium caused the loss of Lgr5+ stem cells due to Cu deficiency. ZnT1, therefore, functions as a dual Zn and Cu transporter and potentially serves as a target for using Zn in the treatment of Wilson's disease caused by Cu overload.
铜 (Cu) 是几种必需代谢酶的辅助因子。铜稳态失调会导致威尔逊病等遗传疾病。在这里，我们表明，锌转运蛋白 1（ZnT1），已知将锌（Zn）从细胞内排出，也介导 Cu 进入细胞，并需要 Cu 诱导的细胞死亡，铜死亡。结构分析和功能表征表明，Cu 和 Zn 共享相同的主要结合位点，允许 Zn 竞争 Cu 摄取。在 ZnT 成员中，ZnT1 具有独特的亚基间二硫键，稳定了两个前体的外向开放构象，从而促进了有效的 Cu 转运。肠上皮细胞中 ZnT1 基因的特异性敲除导致 Lgr5+干细胞因 Cu 缺乏而丢失。因此，ZnT1 作为一种双 Zn 和 Cu 转运蛋白发挥作用，并可能成为利用 Zn 治疗由 Cu 过载引起的威尔逊病的靶点。
