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From Proteopedia
ZnT1 CTD regulation
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 is an essential trace element vital for cellular function, and its homeostasis is tightly regulated. ZnT1, a cation diffusion facilitator (CDF) family member, extrudes excess zinc across the mammalian plasma membrane, making it a major part of the zinc homeostasis system. While ZnT1 shares structural similarities with other CDF proteins, the role of its C-terminal domain (CTD) in zinc transport remains unclear. We used structural determination and comparative analysis, site-directed mutagenesis, and functional zinc transport assays to demonstrate that the ZnT1 CTD is a regulatory element. The regulation involves a distinct CTD conformational change upon structural, non-transported zinc binding. The observed conformational changes in the mammalian CTD are different from those observed in prokaryotic CDFs. The effects of mutating the CTD zinc-binding site on zinc transport are consistent with a hierarchical trend in the CTD regulatory role, possibly due to the importance of the CTD zinc-binding residues. This is in contrast to mutations designed to induce different prokaryotic CTD conformations that do not affect transport. Finally, we show that the unstructured extension of the CTD is dispensable, and its deletion does not affect zinc transport. Our findings establish the CTD as a key modulator of ZnT1 activity, revealing both conserved and divergent regulatory strategies across species. By elucidating ZnT1's transport regulation, this study advances our understanding of how structurally related transporters fine-tune zinc homeostasis across biological systems. Structural and functional insights of ZnT1 C-terminal domain as a regulator of zinc transport.,Ben Yosef TE, Kass I, Shahar A, Eremenko E, Monsonego A, Gitler D, Moran A, Zarivach R Sci Rep. 2025 Jul 24;15(1):26920. doi: 10.1038/s41598-025-07351-5. PMID:40707521[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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