Identification of a Putative Metal Transporter in the Apicoplast of Malaria Parasites

Abstract

Plasmodium falciparum malaria parasites harbor an essential plastid organelle, called the apicoplast, which produces key metabolites required for organelle function and parasite viability. Apicoplast functions depend on iron and other metals, but the membrane transporters that mediate metal import into this organelle have been challenging to identify. Tetracycline antibiotics, including doxycycline, specifically target the apicoplast and can exhibit metal-dependent activity. Using tetracycline-affinity proteomics, we identified a doxycycline-interacting, uncharacterized transmembrane protein (UCT) targeted to the apicoplast periphery but not proteolytically processed. Although lacking sequence similarity to proteins of known function, UCT has a predicted structure with high similarity to pentameric CorA-family metal transporters that mediate metal uptake in other organisms. Functional tests revealed that UCT is dispensable for blood-stage asexual parasites, suggesting that the apicoplast has evolved redundant mechanisms for metal uptake. UCT knockdown in gametocytes, however, impairs the development of sexual parasites, which are critical for mosquito transmission. Our study identifies an apicoplast membrane protein with localization and structural properties that predict a role in metal transport into this key organelle. This discovery can provide a biochemical springboard to unravel broader apicoplast mechanisms of metal uptake across multiple stages of parasite development, including mosquito-stage parasites that display heightened UCT expression.