Proteomic High Affinity Zn2+ Trafficking: Where Does Metallothionein Fit in?

Abstract

The cellular constitution of Zn-proteins and Zn-dependent signaling depend on the capacity of Zn2+ to find specific binding sites in the face of a plethora of other high affinity ligands. The most prominent of these is metallothionein (MT). It serves as a storage site for Zn2+ under various conditions, and has chemical properties that support a dynamic role for MT in zinc trafficking. Consistent with these characteristics, changing the availability of zinc for cells and tissues causes rapid alteration of zinc bound to MT. Nevertheless, zinc trafficking occurs in metallothionein-null animals and cells, hypothetically making use of proteomic binding sites to mediate the intracellular movements of zinc. Like metallothionein, the proteome contains a large concentration of proteins that strongly coordinate zinc. In this environment, free Zn2+ may be of little significance. Instead, this review sets forth the basis for the hypothesis that components of the proteome and MT jointly provide the platform for zinc trafficking.

Invited review: Mineral absorption mechanisms, mineral interactions that affect acid–base and antioxidant status, and diet considerations to improve mineral status

“…Metallothionein can be thought of as a special ZnT protein. However, it only slowly gives up Zn to other ZnT proteins for use in the enterocyte or for export from the enterocyte (Petering and Mahim, 2017). Any Zn bound to metallothionein at the time the enterocyte dies and is sloughed off will be excreted with the feces (Chesters, 1997).…”

Ternary Zn(II) Complexes of Fluorescent Zinc Probes Zinpyr-1 and Zinbo-5 with the Low Molecular Weight Component of Exchangeable Cellular Zinc Pool

“…The stability constants of these complexes are much lower than those represented by zinc proteome, e.g. metallothioneins and zinc finger proteins. − Thus, these low molecular weight ligands (LMWLs) are rarely taken into account as players in intracellular Zn­(II) chemistry. However, they are present at significant concentrations (typically 10 –5 –10 –2 M) − under physiological conditions.…”

Impact of the Cellular Zinc Status on PARP-1 Activity and Genomic Stability in HeLa S3 Cells

“…Thus, in case of oxidative stress, zinc is released out of zincosomes and metallothioneins, increasing the intracellular labile zinc concentration 36−40 Taken together, the correlation of the intracellular zinc status, especially with respect to the level of "labile" or exchangeable zinc, on poly(ADP-ribosyl)ation provides a novel aspect in zinc signaling, namely the activation of a specific DNA repair reaction which is silent on normal cellular conditions and only activated on conditions of DNA and oxidative stress, the latter of which may result in zinc release for example from metallothionein but also from other LMWLs and proteomic binding sites. 42,43 As a further parameter of genotoxicity, both zinc excess and zinc deficiency provoked an increase in DNA strand breaks, but these effects were restricted to cytotoxic concentrations of either ZnCl 2 (300 μM; data not shown) or TPEN (5 μM). This genotoxic effect of TPEN could be explained by an interaction of TPEN with zinc-dependent proteins and enzymes involved in ROS detoxification and/or repair, depleting them from zinc and resulting in disturbed functions.…”

“…Also, it was excluded that the diminished PARP activity was caused by PARP cleavage in the presence of TPEN. Taken together, the correlation of the intracellular zinc status, especially with respect to the level of “labile” or exchangeable zinc, on poly­(ADP-ribosyl)­ation provides a novel aspect in zinc signaling, namely the activation of a specific DNA repair reaction which is silent on normal cellular conditions and only activated on conditions of DNA damage and oxidative stress, the latter of which may result in zinc release for example from metallothionein but also from other LMWLs and proteomic binding sites. , …”