Functional analysis of protein kinase CK2 of the human malaria parasite Plasmodium falciparum.
Protein kinase CK2 (casein kinase 2) is a eukaryotic serine/threonine protein kinase with multiple substrates and roles in diverse cellular processes, including differentiation, proliferation, and translation. The mammalian holoenzyme consists of two catalytic alpha or alpha' subunits and two regulatory beta subunits. We report the identification and characterization of a Plasmodium falciparum CK2alpha orthologue, PfCK2alpha, and two PfCK2beta orthologues, PfCK2beta1 and PfCK2beta2. Recombinant PfCK2alpha possesses protein kinase activity, exhibits similar substrate and cosubstrate preferences to those of CK2alpha subunits from other organisms, and interacts with both of the PfCK2beta subunits in vitro. Gene disruption experiments show that the presence of PfCK2alpha is crucial to asexual blood stage parasites and thereby validate the enzyme as a possible drug target. PfCK2alpha is amenable to inhibitor screening, and we report differential susceptibility between the human and P. falciparum CK2alpha enzymes to a small molecule inhibitor. Taken together, our data identify PfCK2alpha as a potential target for antimalarial chemotherapeutic intervention.
Holland
Zoë
Z
INSERM U609, Wellcome Centre for Molecular Parasitology, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom.
Prudent
Renaud
R
Reiser
Jean-Baptiste
JB
Cochet
Claude
C
Doerig
Christian
C
D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D016778:Malaria, Falciparum / Q000469:parasitology*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity
D021122:Protein Subunits; D047390:Casein Kinase II