Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells

Abstract

Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses. Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. There are 14 ZIP family members in humans. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology; it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Ten family members have been identified. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential.

Figure 1

Overview of ZIP. (a) Topological model of ZIP. ZIP is composed of 8 TMDs with a large N-terminal domain including a PCD and HRD as well as a CTD. The pseudosymmetric TMs are shown in the same color. Zn²⁺ binds to the active site made up of TMD4 and 5 via the conserved HNXXD and HEXXH motifs. (b) Transport mechanism. ZIP has two major conformations, the inward-open and the outward-open conformations. The PAL motif and TMDs are involved in dimerization.

Figure 2

Overview of ZnT. (a) Topological model of ZnT. TMDs of ZnT are divided into two groups; TM1, 2, 4, and 5 form one bundle and TM3 and 6 form the other bundle. TM2 and TM4 share the Zn²⁺ binding site via HXXXD motifs. TM3 and 6 trigger the charge interlock that stabilizes the dimeric conformation. (b) Transport mechanism. ZnT has two major conformations, the inward-open and outward-open conformations, similar to ZIP. CTDs contain 4 Zn²⁺ that are not transported across the lipid bilayer but contribute to the stabilization of dimerization in a zinc-dependent manner. In the YiiP crystal structure, one Zn²⁺ is found in the link between the TMD and CTD (pink circle).