title: Plasmodium falciparum encodes a conserved active inhibitor-2 for Protein Phosphatase type 1: perspectives for novel anti-plasmodial therapy.
abstract: 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 12KTISW16 and 102HYNE105 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.
authors.affiliation: Center for Infection and Immunity of Lille, Inserm U1019-CNRS UMR 8204, University of Lille Nord de France, Institut Pasteur de Lille, 1 Rue du Professeur Calmette, 59019 Lille, Cedex, France. jamal.khalife@pasteur-lille.fr
authors.forename: Aline
authors.initials: A
authors.lastname: Fréville
authors.forename: Katia
authors.initials: K
authors.lastname: Cailliau-Maggio
authors.forename: Christine
authors.initials: C
authors.lastname: Pierrot
authors.forename: Géraldine
authors.initials: G
authors.lastname: Tellier
authors.forename: Hadidjatou
authors.initials: H
authors.lastname: Kalamou
authors.forename: Sophia
authors.initials: S
authors.lastname: Lafitte
authors.forename: Alain
authors.initials: A
authors.lastname: Martoriati
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Pierce
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bodart
authors.forename: Jamal
authors.initials: J
authors.lastname: Khalife
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D003001:Cloning, Molecular; D019295:Computational Biology; D016195:G2 Phase / Q000187:drug effects; D018390:Gene Targeting; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D008969:Molecular Sequence Data; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010271:Parasites / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014981:Xenopus / Q000378:metabolism; D000097847:Protein Phosphatase Inhibitory Proteins
chemical_list: D000962:Antimalarials; D010455:Peptides; D054645:Protein Phosphatase 1; D011506:Proteins; D015800:Protozoan Proteins; C024833:protein phosphatase inhibitor-2; D000097847:Protein Phosphatase Inhibitory Proteins