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Background  It is clear that the coordinated and reciprocal actions of kinases and phosphatases are fundamental in the regulation of development and growth of the malaria parasite. Protein Phosphatase type 1 is a key enzyme playing diverse and essential roles in cell survival. Its dephosphorylation activity/specificity is governed by the interaction of its catalytic subunit (PP1c) with regulatory proteins. Among these, inhibitor-2 (I2) is one of the most evolutionarily ancient PP1 regulators.  In vivo  studies in various organisms revealed a defect in chromosome segregation and cell cycle progression when the function of I2 is blocked.    Results  In this report, we present evidence that  Plasmodium falciparum , the causative agent of the most deadly form of malaria, expresses a structural homolog of mammalian I2, named PfI2. Biochemical,  in vitro  and  in vivo  studies revealed that PfI2 binds PP1 and inhibits its activity. We further showed that the motifs  12 KTISW 16  and  102 HYNE 105  are critical for PfI2 inhibitory activity. Functional studies using the  Xenopus  oocyte model revealed that PfI2 is able to overcome the G2/M cell cycle checkpoint by inducing germinal vesicle breakdown. Genetic manipulations in  P. falciparum  suggest an essential role of PfI2 as no viable mutants with a disrupted  PfI2  gene were detectable. Additionally, peptides derived from PfI2 and competing with RVxF binding sites in PP1 exhibit anti-plasmodial activity against blood stage parasites  in vitro .    Conclusions  Taken together, our data suggest that the PfI2 protein could play a role in the regulation of the  P. falciparum  cell cycle through its PfPP1 phosphatase regulatory activity. Structure-activity studies of this regulator led to the identification of peptides with anti-plasmodial activity against blood stage parasites  in vitro  suggesting that PP1c-regulator interactions could be a novel means to control malaria.

Plasmodium falciparumencodes a conserved active inhibitor-2 for Protein Phosphatase type 1: perspectives for novel anti-plasmodial therapy