ZIP1 Is a Zinc-Selective Transporter with Stage-Dependent Targeting to the Apicoplast and Plasma Membrane in Erythrocytic Parasites.

Replication of the malarial parasite in human erythrocytes requires massive zinc fluxes, necessitating the action of zinc transporters across the parasite plasma and organellar membranes. Although genetic knockout studies have been conducted on a few "orphan" zinc transporters in spp., none of them have been functionally characterized. We used the recombinant Zrt-/Irt-like protein (ZIP1) and specific antibodies generated against it to explore the subcellular localization, function, metal-ion selectivity, and response to cellular zinc levels. ZIP1 expression was enhanced upon the depletion of cytosolic Zn. The protein transitioned from the processed to unprocessed form through blood stages, localizing to the apicoplast in trophozoites and to the parasite plasma membrane in schizonts and gametocytes, indicating stage-specific functional role. The ZIP1 dimer mediated Zn influx in proteoliposomes. It exhibited preferential binding to Zn compared to Fe, with the selectivity for zinc being driven by a C-terminal histidine-rich region conserved only in primate-infecting species.