PfPKB, a novel protein kinase B-like enzyme from Plasmodium falciparum: I. Identification, characterization, and possible role in parasite development.
Extracellular signals control various important functions of a eukaryotic cell, which is often achieved by regulating a battery of protein kinases and phosphatases. Protein Kinase B (PKB) is an important member of the phosphatidylinositol 3-kinase-dependent signaling pathways in several eukaryotes, but the role of PKB in protozoan parasites is not known. We have identified a protein kinase B homologue in Plasmodium falciparum (PfPKB) that is expressed mainly in the schizonts and merozoites. Even though PfPKB shares high sequence homology with PKB catalytic domain, it lacks a pleckstrin homology domain typically found at the N terminus of the mammalian enzyme. Biochemical studies performed to understand the mechanism of PfPKB catalytic activation suggested (i) its activation is dependent on autophosphorylation of a serine residue (Ser-271) in its activation loop region and (ii) PfPKB has an unusual N-terminal region that was found to negatively regulate its catalytic activity. We also identified an inhibitor of PfPKB activity that also inhibits P. falciparum growth, suggesting that this enzyme may be important for the development of the parasite.
Kumar
Amit
A
Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi 110067, India.
Vaid
Ankush
A
Syin
Chiang
C
Sharma
Pushkar
P
D000595:Amino Acid Sequence; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D020134:Catalytic Domain; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D019992:Databases as Topic; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007211:Indoles; D008301:Maleimides; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000201:enzymology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors
D002227:Carbazoles; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012694:Serine; C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; C081021:Go 6976; C487499:PKB protein, Plasmodium falciparum