Studies on the kinome of Plasmodium falciparum and biochemical characterization of atypical protein kinases

Equinet, Leila (2004) Studies on the kinome of Plasmodium falciparum and biochemical characterization of atypical protein kinases. PhD thesis, University of Glasgow.

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Abstract

Despite promising results on efficient vaccine and the development of effective new drugs, malaria continues to kill more than 1-2 million of people each year, and resistance to drugs has become a pressing problem. In the context of new drug discovery, it is important to identify key regulators of the development of the human malaria parasite, Plasmodium falciparum. P. falciparum has a complex life cycle consisting of a succession of ' developmental stages. Some of these stages are characterised by intense cell divisions, while others undergo differentiation accompanied by cell cycle arrest. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in such cellular processes; hence malarial ePK represent potential drug targets. The availability of a genomic database for P. falciparum had permited a systematic analysis of the entire complement of protein kinases encoded in the genome (the so-called "kinome"). The resulting plasmodial kinase set was classified into eukaryotic protein kinase families. During this analysis, a novel subfamily of twenty protein kinases unrelated to any of the ePK families was identified and called FIKK. This new family, localized in subtelomeric regions of the P. falciparum chromosomes, is conserved in the Apicomplexa phylum, but no homologues were found in other organisms so far. The phylogenetic studies of P. falciparum kinases confirmed the presence of two genes encoding atypical CDK(cycin-dependent kinases)-related kinases in the genome, Pfcrk-3 and Pfcrk-4. Comparison of their sequences to those of CDKs from other organisms revealed that in addition to large extensions, Pfcrk-3 and Pfcrk-4 possess two large insertions within the catalytic domain. These extensions and insertions were shown to be expressed in the parasite. The characterisation of these proteins (the FDCK family, Pfcrk-3 and Pfcrk-4) lead to the conclusion that in standard conditions of kinase assay experiments, these proteins do not display any kinase activity in vitro. However, protein-protein interaction studies showed that Pfcrk-3 and Pfcrk-4 are part of in complexes, which display kinase activity.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Christian Doerig
Keywords: Developmental biology, Parasitology
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-71263
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71263

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