Fig. 3

The putative structures of ZnT and ZIP transporters. Left side: the putative topology of ZnT transporters. ZnT transporters efflux Zn from the cytosol to the extracellular space or to the lumen of intracellular compartments. ZnT transporters are thought to have six TMDs consisting of two bundles of a compact four-helix (TMDs I, II, IV, and V) and a two-helix pair (TMDs III and VI). They are thought to function as Y-shaped dimers for Zn transport, based on the structural information of E. coli YiiP (shown in top-left panel, PDB 3H90) [71,72,73,74]. Most ZnT transporters have an indispensable intramembranous Zn-binding site (site A, indicated in magenta circle) consisting of two His (magenta) and two Asp (yellow) residues (HDHD core motif). The position of the His residue (red circle) is speculated to regulate metal substrate specificity. The cytosolic carboxyl-terminal domain (pink square) contains the cytosolic Zn-binding site (site C, indicated in dark green circle), and is thought to consist of two α helixes and three β sheets (αββαβ). The Zn-binding site corresponding to site B in YiiP is omitted because this site is not conserved among ZnT transporters. The cytosolic His-rich loop is indicated in green. The PP motif in the luminal loop in ZnT5 and ZnT7, which is important for TNAP activation [139], is shown in red. Putative Zn chaperon proteins in the cytosol may transfer Zn to the ZnT transporters (see text). Right side: the putative topology of ZIP transporters. This diagram is based on the information available for ZIP4, which is in the LIV-1 subfamily [93, 95]. ZIP transporters mobilize Zn in a direction opposite to that of ZnT transporters. ZIP transporters are thought to have eight TMDs and to function as dimers (not shown). The His residue (magenta) in TMD V is speculated to form part of an intramembranous Zn-binding site, and this position may be involved in specifying the substrate metal. ZIP transporters of the LIV-1 subfamily are characterized by a long extracellular amino-terminal portion containing the helix-rich domain (HRD, orange) and the PAL motif–containing domain (PCD, blue). A potential metalloprotease motif (HEXPHEXGD) is embedded in TM helix V (pale green). Some ZIP transporters have a His cluster (purple) in the cytosolic loop between TMDs III and IV