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

Autor: Sophia Lafitte, Raymond J. Pierce, Jamal Khalife, Géraldine Tellier, Katia Cailliau-Maggio, Jean-François Bodart, Christine Pierrot, Hadidjatou Kalamou, Aline Fréville, Alain Martoriati
Přispěvatelé: BMC, Ed., Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Régulation des Signaux de Division, Université de Lille, Sciences et Technologies, This work is supported by Inserm, CNRS and Université Lille Nord de France., Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Plasmodium
Physiology
Xenopus
[SDV]Life Sciences [q-bio]
Amino Acid Motifs
Protozoan Proteins
Plant Science
Chromosome segregation
Mice
Structural Biology
Protein Phosphatase 1
Protein Interaction Mapping
Cloning
Molecular
Malaria
Falciparum
chemistry.chemical_classification
0303 health sciences
Agricultural and Biological Sciences(all)
biology
Kinase
030302 biochemistry & molecular biology
PP1
Inhibitor-2
3. Good health
Cell biology
[SDV] Life Sciences [q-bio]
Protein Transport
Gene Targeting
General Agricultural and Biological Sciences
Biotechnology
Research Article
Protein Binding
RVXF motifs
G2 Phase
Protein subunit
Phosphatase
Molecular Sequence Data
Plasmodium falciparum
Mitosis
G2/M cell cycle
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
General Biochemistry
Genetics and Molecular Biology
Dephosphorylation
03 medical and health sciences
Antimalarials
Two-Hybrid System Techniques
Animals
Humans
Parasites
Amino Acid Sequence
[SDV.BC] Life Sciences [q-bio]/Cellular Biology
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Life Cycle Stages
Biochemistry
Genetics and Molecular Biology(all)
Computational Biology
Proteins
Cell Biology
biology.organism_classification
Enzyme
chemistry
Oocytes
Peptides
Function (biology)
Developmental Biology
Zdroj: BMC Biology
BMC Biology, 2013, 11 (1), pp.80. ⟨10.1186/1741-7007-11-80⟩
BMC Biology, BioMed Central, 2013, 11 (1), pp.80. ⟨10.1186/1741-7007-11-80⟩
ISSN: 1741-7007
DOI: 10.1186/1741-7007-11-80
Popis: 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.
Databáze: OpenAIRE
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