Physiologic implications of metal-ion transport by ZIP14 and ZIP8

Abstract

Zinc, iron, and manganese are essential trace elements that serve as catalytic or structural components of larger molecules that are indispensable for life. The three metal ions possess similar chemical properties and have been shown to compete for uptake in a variety of tissues, suggesting that they share common transport proteins. Two likely candidates are the recently identified transmembrane proteins ZIP14 and ZIP8, which have been shown to mediate the cellular uptake of a number of divalent metal ions including zinc, iron, manganese, and cadmium. Although knockout and transgenic mouse models are beginning to define the physiologic roles of ZIP14 and ZIP8 in the handling of zinc and cadmium, their roles in the metabolism of iron and manganese remain to be defined. Here we review similarities and differences in ZIP14 and ZIP8 in terms of structure, metal transport, tissue distribution, subcellular localization, and regulation. We also discuss potential roles of these proteins in the metabolism of zinc, iron, manganese, and cadmium as well as recent associations with human diseases.

Fig. 1

Similarity of ZIP14 and ZIP8 proteins. A) Dendogram showing relationships of the ZIP family proteins. ZIP subfamily groupings and amino acid lengths are also indicated. B) Amino acid sequences for murine ZIP14 (NP_001121903.1) and ZIP8 (NP_001128618.1) were obtained from GenBank and aligned by using Vector NTI. Dark gray shading indicates identical amino acids; light gray shading indicates conservative substitutions. Putative transmembrane (TM) domains, indicated by Roman numerals, were predicted by using MEMSAT-SVM and predictions by Taylor et al. (2005). Also indicated are the histidine-rich repeat region (HXHXHXHX) between TM domains III and IV, the metalloprotease motif in TM domain V (HEXXH), and the experimentally verified N-linked glycosylation sites (*) for ZIP14 and ZIP8 (unpublished data, N. Zhao, S. Jenkitkasemwong, and M.D. Knutson).