Abstract
The two organelles, apicoplast and mitochondrion, of the malaria parasite Plasmodium falciparum have unique morphology in liver and blood stages; they undergo complex branching and looping prior to division and segregation into daughter merozoites. Little is known about the molecular processes and proteins involved in organelle biogenesis in the parasite. We report the identification of an AAA+/FtsH protease homolog (PfFtsH1) that exhibits ATP- and Zn2+-dependent protease activity. PfFtsH1 undergoes processing, forms oligomeric assemblies, and is associated with the membrane fraction of the parasite cell. Generation of a transfectant parasite line with hemagglutinin-tagged PfFtsH1, and immunofluorescence assay with anti-PfFtsH1 Ab demonstrated that the protein localises to P. falciparum mitochondria. Phylogenetic analysis and the single transmembrane region identifiable in PfFtsH1 suggest that it is an i-AAA like inner mitochondrial membrane protein. Expression of PfFtsH1 in Escherichia coli converted a fraction of bacterial cells into division-defective filamentous forms implying a sequestering effect of the Plasmodium factor on the bacterial homolog, indicative of functional conservation with EcFtsH. These results identify a membrane-associated mitochondrial AAA+/FtsH protease as a candidate regulatory protein for organelle biogenesis in P. falciparum.
Highlights
Plasmodium spp., the causal agents of malaria, contain two endosymbiotic organelles- a mitochondrion, and a relic plastid called the apicoplast
A cytokinesis defect observed upon expression of recombinant PfFtsH in E. coli suggests a role for the protein in mitochondrial biogenesis and division in Plasmodium
FtsH metalloproteases are ubiquitous in Bacteria and Eukarya and several FtsH homologs that localise exclusively in plastids or mitochondria have been identified in eukaryotes
Summary
Plasmodium spp., the causal agents of malaria, contain two endosymbiotic organelles- a mitochondrion, and a relic plastid called the apicoplast. The mitochondria are elongated or branched before erythrocytic schizogony with frequent contact points with the plasma membrane and attain a highly branched morphology in the late blood schizont stages [24] These mitochondria often contain looped regions, where the organelle apparently fuses back upon itself. FtsH belongs to the AAA+ (ATPases Associated with various cellular Activities) family of metalloproteases [33] It was discovered as a mutant responsible for the defective growth of E. coli [34,35]. FtsH proteins are found in prokaryotes as well as mitochondria and chloroplasts of eukaryotes Proteins of this family participate in cellular activities like protein degradation, regulation of the cell cycle, protein translocation and organelle biogenesis [36,37]. A cytokinesis defect observed upon expression of recombinant PfFtsH in E. coli suggests a role for the protein in mitochondrial biogenesis and division in Plasmodium
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