title: Plasmodium falciparum NIMA-related kinase Pfnek-1: sex specificity and assessment of essentiality for the erythrocytic asexual cycle.
abstract: The Plasmodium falciparum kinome includes a family of four protein kinases (Pfnek-1 to -4) related to the NIMA (never-in-mitosis) family, members of which play important roles in mitosis and meiosis in eukaryotic cells. Only one of these, Pfnek-1, which we previously characterized at the biochemical level, is expressed in asexual parasites. The other three (Pfnek-2, -3 and -4) are expressed predominantly in gametocytes, and a role for nek-2 and nek-4 in meiosis has been documented. Here we show by reverse genetics that Pfnek-1 is required for completion of the asexual cycle in red blood cells and that its expression in gametocytes in detectable by immunofluorescence in male (but not in female) gametocytes, in contrast with Pfnek-2 and Pfnek-4. This indicates that the function of Pfnek-1 is non-redundant with those of the other members of the Pfnek family and identifies Pfnek-1 as a potential target for antimalarial chemotherapy. A medium-throughput screen of a small-molecule library provides proof of concept that recombinant Pfnek-1 can be used as a target in drug discovery.
authors.affiliation: INSERM U609, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.|INSERM-EPFL Joint Laboratory, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, GHI-SV-EPFL Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Dorin-Semblat
authors.affiliation: Cell Cycle Group, C.N.R.S., Station Biologique, 29680 Roscoff, Bretagne, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: INSERM U609, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.|INSERM-EPFL Joint Laboratory, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, GHI-SV-EPFL Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Semblat
authors.affiliation: INSERM U609, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.|INSERM-EPFL Joint Laboratory, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, GHI-SV-EPFL Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sicard
authors.affiliation: INSERM U609, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.|INSERM-EPFL Joint Laboratory, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, GHI-SV-EPFL Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Reininger
authors.affiliation: Biochemistry, University of Kwazulu-Natal, PB X01 Scottsville, South Africa.
authors.forename: Dean
authors.initials: D
authors.lastname: Goldring
authors.affiliation: Department of Molecular Biology and Microbiology, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Patterson
authors.affiliation: Infection and Immunity, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
authors.forename: Neils
authors.initials: N
authors.lastname: Quashie
authors.affiliation: Department of Molecular Biology and Microbiology, University of Central Florida, 12722 Research Parkway, Orlando, FL 32826, USA.
authors.forename: Debopam
authors.initials: D
authors.lastname: Chakrabarti
authors.affiliation: Cell Cycle Group, C.N.R.S., Station Biologique, 29680 Roscoff, Bretagne, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: INSERM U609, Wellcome Trust Centre for Molecular Parasitology, University of Glasgow, Glasgow G12 8TA, UK.|INSERM-EPFL Joint Laboratory, Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, GHI-SV-EPFL Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology*; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008297:Male; D005810:Multigene Family; D000072380:NIMA-Related Kinase 1; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D012100:Reproduction, Asexual; D013045:Species Specificity
chemical_list: D018797:Cell Cycle Proteins; D015800:Protozoan Proteins; C000606914:NEK1 protein, human; D000072380:NIMA-Related Kinase 1; D017346:Protein Serine-Threonine Kinases