Structural insights into human zinc transporter ZnT1 mediated Zn2+ efflux

作者：Yonghui Long, Zhini Zhu, Zixuan Zhou, Chuanhui Yang, Yulin Chao, Y. Wang, Qingtong Zhou, Ming‐Wei Wang, Qianhui Qu · 发表于：EMBO Reports · 年份：2024 · DOI：10.1038/s44319-024-00287-3 · 被引用次数：16 · 研究领域：Trace Elements in Health、Heavy Metal Exposure and Toxicity、Drug Transport and Resistance Mechanisms

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 2+ translocation is coupled with H + or Ca 2+ 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 2+ ions coordinated at the TMD binding site by distinct compositions. At pH 6.0, ZnT1 complexed with Zn 2+ 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.