Structural insights into human zinc transporter ZnT1 mediated Zn²⁺ efflux.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-10-10 DOI:10.1038/s44319-024-00287-3

Yonghui Long, Zhini Zhu, Zixuan Zhou, Chuanhui Yang, Yulin Chao, Yuwei Wang, Qingtong Zhou, Ming-Wei Wang, Qianhui Qu

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Abstract

Zinc transporter 1 (ZnT1), the principal carrier of cytosolic zinc to the extracellular milieu, is important for cellular zinc homeostasis and resistance to zinc toxicity. Despite recent advancements in the structural characterization of various zinc transporters, the mechanism by which ZnTs-mediated Zn²⁺ translocation is coupled with H⁺ or Ca²⁺ remains unclear. To visualize the transport dynamics, we determined the cryo-electron microscopy (cryo-EM) structures of human ZnT1 at different functional states. ZnT1 dimerizes via extensive interactions between the cytosolic (CTD), the transmembrane (TMD), and the unique cysteine-rich extracellular (ECD) domains. At pH 7.5, both protomers adopt an outward-facing (OF) conformation, with Zn²⁺ ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn²⁺ exhibits various conformations [OF/OF, OF/IF (inward-facing), and IF/IF]. These conformational snapshots, together with biochemical investigation and molecular dynamic simulations, shed light on the mechanism underlying the proton-dependence of ZnT1 transport.

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人类锌转运体 ZnT1 介导的 Zn2+ 外流的结构研究。

锌转运体 1（ZnT1）是将细胞膜锌转运到细胞外环境的主要载体，对细胞锌平衡和抵抗锌毒性非常重要。尽管最近在各种锌转运体的结构表征方面取得了进展，但 ZnTs 介导的 Zn2+ 转运与 H+ 或 Ca2+ 的耦合机制仍不清楚。为了使转运动力学可视化，我们测定了人 ZnT1 在不同功能状态下的冷冻电镜（cryo-EM）结构。ZnT1 通过胞膜结构域（CTD）、跨膜结构域（TMD）和独特的富半胱氨酸胞外结构域（ECD）之间的广泛相互作用而形成二聚体。在 pH 值为 7.5 时，两种原体都采用外向型（OF）构象，Zn2+ 离子以不同的成分配位在 TMD 结合位点。在 pH 值为 6.0 时，ZnT1 与 Zn2+ 复合物呈现出多种构象 [OF/OF、OF/IF（内向）和 IF/IF]。这些构象快照以及生化研究和分子动力学模拟揭示了 ZnT1 转运的质子依赖性机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.