title: Plasmodium falciparum inhibitor-3 homolog increases protein phosphatase type 1 activity and is essential for parasitic survival.
abstract: Growing evidence indicates that the protein regulators governing protein phosphatase 1 (PP1) activity have crucial functions because their deletion drastically affects cell growth and division. PP1 has been found to be essential in Plasmodium falciparum, but little is known about its regulators. In this study, we have identified a homolog of Inhibitor-3 of PP1, named PfI3. NMR analysis shows that PfI3 belongs to the disordered protein family. High affinity interaction of PfI3 and PfPP1 is demonstrated in vitro using several methods, with an apparent dissociation constant K(D) of 100 nm. We further show that the conserved (41)KVVRW(45) motif is crucial for this interaction as the replacement of the Trp(45) by an Ala(45) severely decreases the binding to PfPP1. Surprisingly, PfI3 was unable to rescue a yeast strain deficient in I3 (Ypi1). This lack of functional orthology was supported as functional assays in vitro have revealed that PfI3, unlike yeast I3 and human I3, increases PfPP1 activity. Reverse genetic approaches suggest an essential role of PfI3 in the growth and/or survival of blood stage parasites because attempts to obtain knock-out parasites were unsuccessful, although the locus of PfI3 is accessible. The main localization of a GFP-tagged PfI3 in the nucleus of all blood stage parasites is compatible with a regulatory role of PfI3 on the activity of nuclear PfPP1.
authors: 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.
authors: Aline
authors: A
authors: Fréville
authors: Isabelle
authors: I
authors: Landrieu
authors: M Adelaida
authors: MA
authors: García-Gimeno
authors: Jérôme
authors: J
authors: Vicogne
authors: Muriel
authors: M
authors: Montbarbon
authors: Benjamin
authors: B
authors: Bertin
authors: Alexis
authors: A
authors: Verger
authors: Hadidjatou
authors: H
authors: Kalamou
authors: Pascual
authors: P
authors: Sanz
authors: Elisabeth
authors: E
authors: Werkmeister
authors: Christine
authors: C
authors: Pierrot
authors: Jamal
authors: J
authors: Khalife
mesh_terms: D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D015800:Protozoan Proteins; D054645:Protein Phosphatase 1