title: Malaria protein kinase CK2 (PfCK2) shows novel mechanisms of regulation.
abstract: Casein kinase 2 (protein kinase CK2) is a conserved eukaryotic serine/theronine kinase with multiple substrates and roles in the regulation of cellular processes such as cellular stress, cell proliferation and apoptosis. Here we report a detailed analysis of the Plasmodium falciparum CK2, PfCK2, demonstrating that this kinase, like the mammalian orthologue, is a dual specificity kinase able to phosphorylate at both serine and tyrosine. However, unlike the human orthologue that is auto-phosphorylated on tyrosine within the activation loop, PfCK2 shows no activation loop auto-phosphorylation but rather is auto-phosphorylated at threonine 63 within subdomain I. Phosphorylation at this site in PfCK2 is shown here to regulate the intrinsic kinase activity of PfCK2. Furthermore, we generate an homology model of PfCK2 in complex with the known selective protein kinase CK2 inhibitor, quinalizarin, and in so doing identify key co-ordinating residues in the ATP binding pocket that could aid in designing selective inhibitors to PfCK2.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Graciotti
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Alam
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
authors.forename: Lev
authors.initials: L
authors.lastname: Solyakov
authors.affiliation: Department of Biochemistry, University of Leicester, Leicester, United Kingdom.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmid
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Glenn
authors.initials: G
authors.lastname: Burley
authors.affiliation: The Protein Nucleic Acid Chemistry Laboratory, University of Leicester, Leicester, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bottrill
authors.affiliation: Department of Microbiology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Doerig
authors.affiliation: Department of Chemistry, University of Leicester, Leicester, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Cullis
authors.affiliation: Medical Research Council Toxicology Unit, University of Leicester, Leicester, United Kingdom.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000880:Anthraquinones / Q000737:chemistry; D001665:Binding Sites; D047390:Casein Kinase II / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000201:enzymology*; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
chemical_list: D000880:Anthraquinones; D015800:Protozoan Proteins; C543211:1,2,5,8-tetrahydroxy anthraquinone; D000255:Adenosine Triphosphate; D047390:Casein Kinase II