Abstract
Zinc is an essential cofactor for the activity and folding of up to ten percent of mammalian proteins and can modulate the function of many others. Because of the pleiotropic effects of zinc on every aspect of cell physiology, deficits of cellular zinc content, resulting from zinc deficiency or excessive rise in its cellular concentration, can have catastrophic consequences and are linked to major patho-physiologies including diabetes and stroke. Thus, the concentration of cellular zinc requires establishment of discrete, active cellular gradients. The cellular distribution of zinc into organelles is precisely managed to provide the zinc concentration required by each cell compartment. The complexity of zinc homeostasis is reflected by the surprisingly large variety and number of zinc homeostatic proteins found in virtually every cell compartment. Given their ubiquity and importance, it is surprising that many aspects of the function, regulation, and crosstalk by which zinc transporters operate are poorly understood. In this mini-review, we will focus on the mechanisms and players required for generating physiologically appropriate zinc gradients across the plasma membrane and vesicular compartments. We will also highlight some of the unsolved issues regarding their role in cellular zinc homeostasis.
Highlights
The uniqueness of zinc, in contrast to other abundant transition metals in the body, e.g., Fe3+ and Cu2+, is that it lacks redox activity
These paradoxical aspects of cellular zinc dictate that it be distributed in highly regulated gradients with respect to the plasma membrane and intracellular compartments
The complexity and importance of zinc homeostasis is reflected by the large number of proteins that are potentially dedicated to Zn2+ transport and buffering (Figure 1), among them, at least ten members of the zinc transporters (ZnTs) (Zn2+ Transporter) family [21], 15 members of the ZIP (i.e., Zn2+-regulated metal transporter, Ironregulated metal transporter-like protein) family [22], and 3 distinct isoforms of metallothionein [23]
Summary
Zinc is an essential cofactor for the activity and folding of up to ten percent of mammalian proteins and can modulate the function of many others. The concentration of cellular zinc requires establishment of discrete, active cellular gradients. The complexity of zinc homeostasis is reflected by the surprisingly large variety and number of zinc homeostatic proteins found in virtually every cell compartment. Given their ubiquity and importance, it is surprising that many aspects of the function, regulation, and crosstalk by which zinc transporters operate are poorly understood. In this mini-review, we will focus on the mechanisms and players required for generating physiologically appropriate zinc gradients across the plasma membrane and vesicular compartments.
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