Abstract
Post-transcriptional and post-translational modifications play a major role in Plasmodium life cycle regulation. Lysine methylation of histone proteins is well documented in several organisms, however in recent years lysine methylation of proteins outside histone code is emerging out as an important post-translational modification (PTM). In the present study we have performed global analysis of lysine methylation of proteins in asexual blood stages of Plasmodium falciparum development. We immunoprecipitated stage specific Plasmodium lysates using anti-methyl lysine specific antibodies that immunostained the asexual blood stage parasites. Using liquid chromatography and tandem mass spectrometry analysis, 570 lysine methylated proteins at three different blood stages were identified. Analysis of the peptide sequences identified 605 methylated sites within 422 proteins. Functional classification of the methylated proteins revealed that the proteins are mainly involved in nucleotide metabolic processes, chromatin organization, transport, homeostatic processes and protein folding. The motif analysis of the methylated lysine peptides reveals novel motifs. Many of the identified lysine methylated proteins are also interacting partners/substrates of PfSET domain proteins as revealed by STRING database analysis. Our findings suggest that the protein methylation at lysine residues is widespread in Plasmodium and plays an important regulatory role in diverse set of the parasite pathways.
Highlights
Plasmodium genome sequencing analysis has revealed existence of a number of methyltransferases, SET-domain-containing proteins and demethylases that are responsible for lysine methylation in the genome[22,33]
To assess the extent of lysine methylation in Plasmodium proteins in asexual blood stages, we tested the reactivity of commercially available anti-mono/di methyl lysine and anti-trimethyl lysine antibodies with the parasite lysate and with intact blood stage P. falciparum parasites by western blot and immunofluorescence analysis respectively
Processes related to intraerythrocytic development of malaria parasite that contributes to malaria associated morbidity and mortality are tightly regulated at transcription as well as translation levels[36,37,38]
Summary
Ten SET domain containing histone lysine methyltransferases (HKMTs), three histone-demethylase orthologs of lysine-specific demethylases (LSD1) and jumonji-C histone demethylases (jHDM) families have been described in Plasmodium These proteins are the targets for novel drug development as the proteins show low sequence similarity to corresponding human counterparts[22,26]. The LC-MS/MS analysis of the immunoprecipitates identified several non-histone methylated Plasmodium proteins linked with diverse functions such as transport, hemostatic processes and chromosome organization. These results suggest an important role of protein lysine methylation in regulation of various P. falciparum biological processes
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