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The interaction of zinc with its transporters has not been well characterized, though transmembrane domains have been identified that are thought to be responsible for the transport function. Free concentrations of zinc within the cell appear to be extremely low and may not constitute a sufficient pool for the supply of zinc to its protein ligands. This suggests the existence of delivery proteins, and this role has been suggested for MT, which has been shown to transfer zinc to apoenzymes in vitro. MT

was originally discovered as a cytoplasmic heavy-metal-binding protein, which was thought to prevent metal toxicity within cells. Additional more significant roles were suggested by the realization that there are multiple MT genes, which have been conserved through evolution. It is a small protein that is unusually rich in cysteine and can bind seven atoms of zinc. MT may influence the subcel-lular distribution and availability of zinc, since its own distribution varies. For example, the nuclear content of MT varies with the cell cycle. MT expression is regulated not only by heavy metals but also by a range of other signals including glucocorticoids, interleukins, and cyclic adenosine monophosphate. In addition, its zinc-binding activity is influenced by the cellular redox state. For example, an increase in the glutathione disulfide-glutathione ratio results in the release of zinc from MT and thus an increase in its availability for other proteins. However, deletion of individual MT genes in mice has not resulted in major pathologies, questioning the significance of these proteins.

Investigation of the mechanism whereby zinc regulates the expression of MT led to the discovery of the single protein known to act as a zinc sensor within mammalian cells, MTF-1 (metal response element (MRE)-binding transcription factor-1). MTF-1 binds to MREs in the promoter region of MT and other genes and regulates their expression.

The ability of MTF-1 to localize to the nucleus and bind to its target genes depends on its zinc content. Thus, an increase in cellular zinc levels results in greater MTF-1 activity and, consequently, increased expression of its target genes. In addition to MT, which will bind more zinc, these include ZnT-1, which will transport zinc out of the cell. These mechanisms underlying cellular zinc homeostasis are illustrated in Figure 2.

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