Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites

Patty B. Chen (1, 1, 2) , Shuai Ding (1, 1, 2) , Gigliola Zanghì (3) , Valérie Soulard (3) , Peter A. P. A. Dimaggio (4) , Matthew J. Fuchter (4) , Salah Mecheri (1, 1, 2) , Dominique Mazier (3, 5) , Artur Scherf (1, 1, 2) , Nicholas A Malmquist (1, 1, 2)

1 Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions
2 INSERM UMR 1201
3 CIMI - Centre d'Immunologie et de Maladies Infectieuses
4 Imperial College London
5 CHU Pitié-Salpêtrière [AP-HP]

Epigenetic control via reversible histone methylation regulates transcriptional activation throughout the malaria parasite genome, controls the repression of multi-copy virulence gene families and determines sexual stage commitment. Plasmodium falciparum encodes ten predicted SET domain-containing protein methyltransferases, six of which have been shown to be refractory to knock-out in blood stage parasites. We have expressed and purified the first recombinant malaria methyltransferase in sufficient quantities to perform a full enzymatic characterization and reveal the ill-defined PfSET7 is an AdoMet-dependent histone H3 lysine methyltransferase with highest activity towards lysines 4 and 9. Steady-state kinetics of the PfSET7 enzyme are similar to previously characterized histone methyltransferase enzymes from other organisms, however, PfSET7 displays specific protein substrate preference towards nucleosomes with pre-existing histone H3 lysine 14 acetylation. Interestingly, PfSET7 localizes to distinct cytoplasmic foci adjacent to the nucleus in erythrocytic and liver stage parasites, and throughout the cytoplasm in salivary gland sporozoites. Characterized recombinant PfSET7 now allows for target based inhibitor discovery. Specific PfSET7 inhibitors can aid in further investigating the biological role of this specific methyltransferase in transmission, hepatic and blood stage parasites, and may ultimately lead to the development of suitable antimalarial drug candidates against this novel class of essential parasite enzymes.

Domaines: Maladies infectieuses; Microbiologie et Parasitologie

Patty B. Chen, Shuai Ding, Gigliola Zanghì, Valérie Soulard, Peter A. P. A. Dimaggio, et al.. Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites. Scientific Reports, 2016, 6, pp.21802. ⟨10.1038/srep21802⟩. ⟨hal-01282028⟩