锌转运体 1 在铜吸收和铜中毒中的功能

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
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引用次数: 0

摘要

铜(Cu)是多种重要代谢酶的辅助因子。铜平衡的破坏会导致遗传性疾病,如威尔逊氏病。在这里,我们发现锌转运体 1(ZnT1)能将锌(Zn)排出细胞外,它还能介导 Cu2+ 进入细胞,并且是 Cu2+ 诱导的细胞死亡(杯突变)所必需的。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,从而使 Zn2+ 能够竞争 Cu2+ 的吸收。在 ZnT 成员中,ZnT1 存在一个独特的亚基间二硫键,可稳定两个原体的外向开放构象,从而促进 Cu2+ 的高效转运。在肠上皮细胞中特异性敲除 ZnT1 基因会导致 Lgr5+ 干细胞因缺铜而丧失。因此,ZnT1具有Zn2+和Cu2+双重转运功能,有可能成为利用Zn2+治疗因Cu超载引起的威尔逊氏病的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Zinc transporter 1 functions in copper uptake and cuproptosis

Zinc transporter 1 functions in copper uptake and cuproptosis

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.

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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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