Abstract
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.
Highlights
From the Eukaryotic Gene Expression Laboratory, National Institute of Immunology, New Delhi 110067, India and ¶Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852
The gene with highest sequence homology was closely related to PfPKB
The other two kinase sequences with around 56% homology to the catalytic domain of Protein Kinase B (PKB) have previously been identified as the cAMP-dependent protein kinase [13] and the cGMP-dependent kinase [5] homologues from P. falciparum
Summary
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 identified an inhibitor of PfPKB activity that inhibits P. falciparum growth, suggesting that this enzyme may be important for the development of the parasite. The major challenge is to understand how these enzymes integrate in cellular machinery of Plasmodium and what roles they play in parasite development The answer to these questions could lead to identification of important signaling pathways involved in the development of this parasite. Studies using a pharmacological inhibitor suggested that PfPKB activity may be important for parasite development
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