清华大学王晓东、郑三多研究小组取得一项新突破。他们的最新研究揭示了锌转运蛋白1在铜吸收和铜还原中起作用。这一研究成果于2024年8月6日发表在国际顶尖学术期刊《细胞—代谢》上。

课题组发现锌转运蛋白1 (ZnT1)，已知将锌(Zn)输出细胞外，也介导Cu2⁺进入细胞，并且是Cu2⁺诱导的细胞死亡、铜增生所必需的。结构分析和功能表征表明，Cu2⁺和Zn²⁺具有相同的主要结合位点，允许Zn²⁺竞争Cu2⁺的摄取。

在ZnT成员中，ZnT1具有独特的亚基间二硫键，可以稳定两个原体的外向开放构象，从而促进有效的Cu2⁺运输。肠道上皮中ZnT1基因的特异性敲除导致了铜缺乏导致Lgr5+干细胞的丢失。因此，ZnT1作为Zn²⁺和Cu2⁺的双重转运体，可能作为使用Zn²⁺用于治疗由Cu过载引起的威尔逊病的靶点。

据了解，铜(Cu)是几种必需代谢酶的辅助因子。铜体内平衡的破坏导致遗传疾病，如威尔逊病。

附：英文原文

Title: Zinc transporter 1 functions in copper uptake and cuproptosis

Author: Yehua Li, Jiahao Ma, Rui Wang, Yuanhanyu Luo, Sanduo Zheng, Xiaodong Wang

Issue&Volume: 2024-08-06

Abstract: Copper (Cu) is a co-factor for several essential metabolic enzymes. Disruption ofCu homeostasis results in genetic diseases such as Wilson's disease. Here, we showthat the zinc transporter 1 (ZnT1), known to export zinc (Zn) out of the cell, alsomediates Cu2+ entry into cells and is required for Cu2+-induced cell death, cuproptosis. Structural analysis and functional characterizationindicate 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 thatstabilizes the outward-open conformations of both protomers to facilitate efficientCu2+ 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.

DOI: 10.1016/j.cmet.2024.07.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00279-1