Abstract:
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 Cu2+ entry into cells and is required for Cu2+-induced cell death, cuproptosis. Structural analysis and functional characterization indicate that Cu2+ and Zn2+ share the same primary binding site, allowing Zn2+ to compete for Cu2+ uptake. Among ZnT members, ZnT1 harbors a unique inter-subunit disulfide bond that stabilizes the outward-open conformations of both protomers to facilitate efficient Cu2+ 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 Zn2+ and Cu2+ transporter and potentially serves as a target for using Zn2+ in the treatment of Wilson\'s disease caused by Cu overload.
摘要:
铜(Cu)是几种必需代谢酶的辅因子。铜稳态的破坏导致遗传性疾病如Wilson病。这里,我们表明锌转运蛋白1(ZnT1),已知将锌(Zn)输出到电池中,也介导Cu2+进入细胞,是Cu2+诱导的细胞死亡所必需的,突起。结构分析和功能表征表明,Cu2+和Zn2+共享相同的主要结合位点,允许Zn2+竞争吸收Cu2+。在ZnT成员中,ZnT1具有独特的亚基间二硫键,可稳定两种原聚体的向外开放构象,以促进有效的Cu2转运。由于Cu缺乏,肠上皮中ZnT1基因的特异性敲除导致Lgr5干细胞的丢失。因此,ZnT1,作为双重Zn2+和Cu2+转运蛋白,并可能作为使用Zn2+治疗由Cu超负荷引起的威尔逊病的靶标。