Title:
ZnT and ZIP: Essential zinc transporters for zinc physiology and biochemistry

Taiho Kambe
Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University

Abstract:
Zinc is an essential trace element required for all living organisms, because it plays a pivotal role as a structural, catalytic and regulatory element in protein functions. Thus, zinc homeostasis is tightly controlled through the highly integrated processes of zinc uptake, sequestration and efflux across the cell membrane, and zinc transport proteins are indispensable for these processes. In general, two solute carrier transporters, Zn transporter (ZnT) and Zrt, Irt-like protein (ZIP), primarily regulate zinc transport in metazoans. ZnT transporters mobilize zinc from the cytosol to the extracellular space and the lumen of intracellular compartments, while ZIP transporters mobilize zinc in the opposite direction. Both ZnT and ZIP transporters enable various zinc-dependent proteins and enzymes to play physiologically important roles in numerous biological processes. Moreover, mobilization of zinc by ZnT and ZIP transporters across the cellular membranes triggers zinc signaling. Thus, loss or reduced function of ZnT and ZIP transporters has been shown to result in a number of inherited diseases, while gain of function or aberrant expression is thought to be involved in diseases such as cancer and neurodegenerative diseases. Recent studies have begun to reveal the molecular mechanisms underlying these processes. However, the mechanisms underlying zinc transport and substrate recognition by these transporters remain to be elucidated. Here, I will discuss the current understanding of ZnT and ZIP transporter functions in physiology and pathogenesis in terms of molecular characteristics, systemic and cellular functions, and disease pathogenesis.

References:
Kambe T, Hashimoto A and Fujimoto S
“Current understanding of ZIP and ZnT zinc transporters in human health and diseases”
Cell. Mol. Life. Sci., 71, 3281-3295, 2014

Fujimoto S, Itsumura N, Tsuji T, Anan Y, Tsuji N, Ogra Y, Kimura T, Miyamae Y, Masuda S, Nagao M and Kambe T
“Cooperative functions of ZnT1, metallothionein and ZnT4 in the cytoplasm are required for full activation of TNAP in the early secretory pathway”
PLoS One, 8, e77445, 2013

Itsumura N, Inamo Y, Okazaki F, Teranishi F, Narita H, Kambe T* and Kodama H (*Corresponding author)
“Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant”
PLoS One, 8, e64045, 2013

Fukunaka A, Kurokawa Y, Teranishi F, Sekler I, Oda K, Ackland M. L, Faundez V, Hiromura M, Masuda S, Nagao M, Enomoto S and Kambe T
“Tissue non-specific alkaline phosphatase is activated via a two-step mechanism by zinc transport complexes in the early secretory pathway”
J. Biol. Chem., 286, 16363-16373, 2011