Plasmodium falciparum, the organism responsible for the most prevalent and most virulent cases of malaria in humans, poses a major burden to the developing world. The parasite is increasingly developing resistance to traditional therapies, such as chloroquine, so the need to determine novel drug targets is more prevalent than ever. One such method involves targeting proteins unique to the malarial proteome that do not have homologues in humans. An especially promising group of targets are protein kinases, which are involved in many different biochemical pathways within the cell. Eukaryotic cell cycle progression is moderated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). These kinases depend on the binding of a cognate regulatory unit (cyclin) in order to enter its activated state. Once activated, these cyclins then mediate phosphorylation events that are crucial to cell cycle advancement . Cyclin Dependent Kinases (CDKs) are common to most eukaryotes and are responsible for regulating the cell cycle of growth and proliferation. Proteins have been previously identified in Plasmodium that have sequence homology to traditional CDK and have a potential function to be classified as "CDK-like" kinases. Three kinases that fit this description are Plasmodium falciparum Kinase 5, 6, and mrk, or MO15- Related Kinase. These kinases are expected to have roles in both malarial growth and regulation of the cell cycle. Bacterial constructs were generated to express and purify recombinant forms of these kinases and potential substrates. Once the potential interactors were isolated, in vitro protein kinase assays were used to validate the interactions to the kinases as substrates. In summary, the study has identified substrates that are directly phosphorylated by PfPK6, and demonstrated that the identified proteins are not directly phosphorylated by PfPK5 and Pfmrk.
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Bachelor of Science (B.S.)
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology - Preprofessional Concentration
Dissertations, Academic -- Medicine; Medicine -- Dissertations, Academic
Length of Campus-only Access
Honors in the Major Thesis
Segarra, Daniel, "Elucidating the Molecular Pathway of Atypical Plasmodium falciparum Kinases through Substrate Characterization" (2015). HIM 1990-2015. 621.