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解析人类锌转运蛋白 ZnT1 介导的锌外排的结构见解。

Structural insights into human zinc transporter ZnT1 mediated Zn efflux.

机构信息

Shanghai Stomatological Hospital, School of Stomatology, Institutes of Biomedical Sciences, Fudan University, 200032, Shanghai, China.

Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan University, 200032, Shanghai, China.

出版信息

EMBO Rep. 2024 Nov;25(11):5006-5025. doi: 10.1038/s44319-024-00287-3. Epub 2024 Oct 10.

DOI:10.1038/s44319-024-00287-3
PMID:39390258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11549101/
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 Zn translocation is coupled with H or Ca 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 Zn ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn 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.

摘要

锌转运蛋白 1（ZnT1）是细胞质锌向细胞外环境转运的主要载体，对于细胞内锌稳态和抵抗锌毒性至关重要。尽管最近在各种锌转运蛋白的结构特征方面取得了进展，但 ZnT 介导的锌转运与 H 或 Ca 的偶联机制仍不清楚。为了可视化运输动力学，我们确定了处于不同功能状态的人 ZnT1 的冷冻电镜（cryo-EM）结构。ZnT1 通过胞质（CTD）、跨膜（TMD）和独特的富含半胱氨酸的细胞外（ECD）结构域之间的广泛相互作用二聚化。在 pH7.5 时，两个前体均采用向外开放（OF）构象，Zn 离子由不同组成的 TMD 结合位点配位。在 pH6.0 时，与 Zn 结合的 ZnT1 表现出各种构象[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，阐明了 ZnT1 转运质子依赖性的机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/a0436d36f4e9/44319_2024_287_Fig11_ESM.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/716e4d26150d/44319_2024_287_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/9c57c792f2ad/44319_2024_287_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/d1c1cea7982b/44319_2024_287_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/4c530003760d/44319_2024_287_Fig7_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/42fb0a49d571/44319_2024_287_Fig8_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/633b9a807644/44319_2024_287_Fig9_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/91a14cb1c8e2/44319_2024_287_Fig10_ESM.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4257/11549101/a0436d36f4e9/44319_2024_287_Fig11_ESM.jpg

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