title: Disruption of a mitochondrial protease machinery in Plasmodium falciparum is an intrinsic signal for parasite cell death.
abstract: The ATP-dependent ClpQY protease system in Plasmodium falciparum is a prokaryotic machinery in the parasite. In the present study, we have identified the complete ClpQY system in P. falciparum and elucidated its functional importance in survival and growth of asexual stage parasites. We characterized the interaction of P. falciparum ClpQ protease (PfClpQ) and PfClpY ATPase components, and showed that a short stretch of residues at the C terminus of PfClpY has an important role in this interaction; a synthetic peptide corresponding to this region antagonizes this interaction and interferes with the functioning of this machinery in the parasite. Disruption of ClpQY function by this peptide caused hindrance in the parasite growth and maturation of asexual stages of parasites. Detailed analyses of cellular effects in these parasites showed features of apoptosis-like cell death. The peptide-treated parasites showed mitochondrial dysfunction and loss of mitochondrial membrane potential. Dysfunctioning of mitochondria initiated a cascade of reactions in parasites, including activation of VAD-FMK-binding proteases and nucleases, which resulted in apoptosis-like cell death. These results show functional importance of mitochondrial proteases in the parasite and involvement of mitochondria in programmed cell death in the malaria parasites.
authors: International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
authors: S
authors: S
authors: Rathore
authors: S
authors: S
authors: Jain
authors: D
authors: D
authors: Sinha
authors: M
authors: M
authors: Gupta
authors: M
authors: M
authors: Asad
authors: A
authors: A
authors: Srivastava
authors: M S
authors: MS
authors: Narayanan
authors: G
authors: G
authors: Ramasamy
authors: V S
authors: VS
authors: Chauhan
authors: D
authors: D
authors: Gupta
authors: A
authors: A
authors: Mohmmed
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D049071:Endopeptidase Clp / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D010455:Peptides; D015800:Protozoan Proteins; D004247:DNA; D010447:Peptide Hydrolases; D049071:Endopeptidase Clp