Mitochondrial localization of the threonine peptidase PfHslV, a ClpQ ortholog in Plasmodium falciparum

Structural and Biochemical Analyses of the Eukaryotic Heat Shock Locus V (HslV) from Trypanosoma brucei

“…For example, there are two potential HslUs in L. donovani, and HslU1 (E9BC50_LEIDB) and HslU2 (E9B9S7_LEIDB) have phenylalanine and tyrosine residues at the critical position, respectively. An HslV ortholog in Plasmodium falciparum also has a tyrosine residue at this site (26). Therefore, we infer that the existence of the tyrosine residue in this position can determine the selection of functional HslU molecules in the eukaryotic HslVU system.…”

“…The dodecameric structure of TbHslV is mediated via hexameric ring-ring interactions, which are mainly hydrophobic in nature (Ile 26 ) contribute to the formation of the dodecamer. These results show that polar interactions, including hydrogen bond and salt bridges, are dominant during formation of the hexameric ring, whereas hydrophobic interactions contribute to the donut shape of the TbHslV dodecamer (Fig.…”

Protein Degradation Systems as Antimalarial Therapeutic Targets

“…PfClpY and PfClpQ proteins are expressed at the trophozoite, schizont, and merozoite stages [84–86]. Bioinformatics analysis predicted mitochondrial localization of PfClpQ, which was confirmed by immunofluorescence assays and immuno-electron microscopy of an enhanced yellow fluorescent protein (EYFP)-tagged PfClpQ [87]. Thus, this protease may be responsible for degrading proteins specifically in the mitochondria.…”

Threonine peptidases as drug targets against malaria

“…Although HslV was always considered a bacterial threonine peptidase, it was recently identified in the genomes of some primordial eukaryotes [20,21,51]. Among them are red, green and glaucophyte algae (Cyanidioschyzon merolae, Ostreococcus, Glaucocystis nostochinearum), amoebae (Dictyostelium discoideum), excavates (Leishmania and Trypanosoma) and chromalveolates (Phytophthora, Thalassiosira pseudonana, Tetrahymena thermophila and Plasmodium), but no opisthokonts (e.g., animals or fungi) were found to possess hslV genes so far [51,52]. In Escherichia coli, HslV is known to participate in the degradation of some regulatory or misfolded proteins [53][54][55].…”

“…However, it is not essential and only under elevated temperature a detectable growth defect can be observed [56]. In Trypanosoma brucei HslV is localized to the kinetoplast [57] and in P. falciparum it was also recently shown that Pf HslV localizes to the mitochondrion in asexual stages [52]. RNAi knockdown of T. brucei HslVU results in defective mitochondrial DNA replication accompanied by a growth defect [57].…”