2.A.5 The Zinc (Zn²⁺)-Iron (Fe²⁺) Permease (ZIP) Family

Most members of the ZIP family consist of 220-650 amino acyl residues with eight putative transmembrane spanners. However, LIV1 of man has been reported to have only 6 TMSs, although it exhibits 8 hydrophobic peaks, and the IAA-alanine resistance protein 1 (Iar1 of A. thaliana) also exhibits 8 TMSs (Lasswell et al., 2000). They are derived from animals, plants, yeast, bacteria and archaea. They comprise a diverse family, with several paralogues in any one organism (e.g., 14 in mammals, at least 5 in Caenorhabditis elegans and Arabidopsis thaliana, and two in Saccharomyces cervisiae). The various mammalian paralogues fall into four subfamilies and are found in a variety of cell types, cell locations and tissues, and some are responsive to hormones and cytokines (Dempski 2012). Thus, Zip6 (LIV1) is estrogen responsive in breast cancer cells and is related to metastasis in lymph nodes. Zip8 (Big M103) is TNFα and endotoxin induced in monocytes. The two S. cerevisiae proteins, Zrt1 and Zrt2, both probably transport Zn²⁺ with high specificity, but Zrt1 transports Zn²⁺ with ten-fold higher affinity than Zrt2. Some members of the ZIP family have been shown to transport Zn²⁺ while others transport Fe²⁺, and a few have been shown to transport a range of metal ions. One human protein member of the ZIP family is designated 'growth arrest inducible gene product,' but its presumed transport activity has not been identified. A second human protein, Zip4, is a Zn²⁺ uptake permease and a disease protein (Cousins et al., 2006). Histidine-rich repeats are found in extracellular N- and C-termini as well as a long intracellular loop, and Zip14 has an extra extracellular his-rich loop. One family of mammalian Zip proteins (the LZT family) has a metaprotease motif (HEXPHEXGD) that may allow them to function as matrix metaloproteases. Zip10 has C₂H₂ zinc finger and cytochrome c motifs in its first TMS (Cousins et al., 2006).

The energy source for transport has not been characterized, but these systems probably function as secondary carriers. They do not require ATP (Cousins et al., 2006). In one study, uptake of Zn²⁺ via the hZip2 permease was energy independent, independent of Na⁺ and K⁺ gradients, but stimulated by HCO₃^- (Gaither and Eide, 2000). The authors propose a Zn²⁺:HCO₃^- symport mechanism. hZip1 is the major Zn²⁺ uptake system in many human tissues (Gaither and Eide, 2001). The N-terminal regions are novel substrate selectors in the ZIP family of transporters (Nishida et al., 2011).

Mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth, and connective tissues, reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS), of some features of osteogenesis imperfecta and Zn deficient disorders. The Zip13 knockout (Zip13-KO) mice show defects in the function of osteoblasts, chondrocytes, odontoblasts and fibroblasts. Zip13 protein is localized to the Golgi in the corresponding cells. Impairment in BMP and TGF-beta signaling were observed in Zip13-KO cells (Fukada et al., 2008).

ZIP5, ZIP6, ZIP7, and ZIP10 in rat liver are regulated by iron. They may play a role in hepatic iron/metal homeostasis during iron deficiency and overload (Nam and Knutson, 2012).

The generalized transport reaction for members of the ZIP family is:

Me²⁺ (out) + (pmf) → Me²⁺ (in).