Abstract
Phosphatidylinositol 3-phosphate (PI3P) is a key ligand for recruitment of endosomal regulatory proteins in higher eukaryotes. Subsets of these endosomal proteins possess a highly selective PI3P binding zinc finger motif belonging to the FYVE domain family. We have identified a single FYVE domain-containing protein in Plasmodium falciparum which we term FCP. Expression and mutagenesis studies demonstrate that key residues are involved in specific binding to PI3P. In contrast to FYVE proteins in other organisms, endogenous FCP localizes to a lysosomal compartment, the malaria parasite food vacuole (FV), rather than to cytoplasmic endocytic organelles. Transfections of deletion mutants further indicate that FCP is essential for trophozoite and FV maturation and that it traffics to the FV via a novel constitutive cytoplasmic to vacuole targeting pathway. This newly discovered pathway excludes the secretory pathway and is directed by a C-terminal 44-amino acid peptide domain. We conclude that an FYVE protein that might be expected to participate in vesicle targeting in the parasite cytosol instead has a vital and functional role in the malaria parasite FV.
Highlights
Malaria parasites inflict a tremendous global burden on the health and productivity of human kind
Sequencing of FCP cDNA confirmed a lack of introns, and comparison of the amino acid sequence with other orthologous counterparts indicated that FCP was highly conserved with 70 – 80% amino acid identity within the malaria parasite genus Plasmodium (Fig. 1A)
Trafficking to the apicoplast has been found to use an N-terminal pre-sequence [36, 37]. This bipartite sorting signal consists of an N-terminal signal peptide for entry into the secretory pathway via the ER followed by an apicoplast membrane transit peptide that permits transit across the membranes of the apicoplast [37]
Summary
Phosphatidylinositol 3-phosphate (PI3P) is a key ligand for recruitment of endosomal regulatory proteins in higher eukaryotes Subsets of these endosomal proteins possess a highly selective PI3P binding zinc finger motif belonging to the FYVE domain family. In contrast to FYVE proteins in other organisms, endogenous FCP localizes to a lysosomal compartment, the malaria parasite food vacuole (FV), rather than to cytoplasmic endocytic organelles. Various other endosomal regulatory proteins bind PI3P and thereby localize to endocytic compartments in yeast and mammals [9]. Many among these including the early endosomal autoantigen-1 (EEA1) contain a highly selective PI3P binding zinc finger motif belonging to the FYVE domain family (conserved in Fab, YOTB, Vac, and EEA1) [9]. By identifying the domain responsible for targeting to the FV, we explain this unexpected result but identify a new direct trafficking pathway between the parasite cytosol and the parasite FV
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