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Cryo-EM structure of human ZnT1 WT, in the presence of zinc, determined in an outward-facing conformation
Structural highlights
FunctionZNT1_HUMAN Zinc ion:proton antiporter that could function at the plasma membrane mediating zinc efflux from cells against its electrochemical gradient protecting them from intracellular zinc accumulation and toxicity (PubMed:31471319). Alternatively, could prevent the transport to the plasma membrane of CACNB2, the L-type calcium channels regulatory subunit, through a yet to be defined mechanism. By modulating the expression of these channels at the plasma membrane, could prevent calcium and zinc influx into cells. By the same mechanism, could also prevent L-type calcium channels-mediated heavy metal influx into cells (By similarity). In some cells, could also function as a zinc ion:proton antiporter mediating zinc entry into the lumen of cytoplasmic vesicles. In macrophages, can increase zinc ions concentration into the lumen of cytoplasmic vesicles containing engulfed bacteria and could help inactivate them (PubMed:32441444).[UniProtKB:Q62720][1] [2] Publication Abstract from PubMedZinc 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. Structural insights into human zinc transporter ZnT1 mediated Zn(2+) efflux.,Long Y, Zhu Z, Zhou Z, Yang C, Chao Y, Wang Y, Zhou Q, Wang MW, Qu Q EMBO Rep. 2024 Oct 10. doi: 10.1038/s44319-024-00287-3. PMID:39390258[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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