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• W3000230855 abstract "Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), also known as sleeping sickness and Animal African Trypanosomiasis (AAT) or nagana in livestock, which results in major health and economic burdens in Sub-Saharan Africa. Although possible treatments are available, they possess several disadvantages as toxicity, high costs of the drugs, difficulty in administration and the development of drug resistance by the parasites complicate timely treatment. The life cycle of the parasite is complex, involving a mammalian host and an insect vector (tsetse fly, Glossina spp.). A previous RNAi screen (Jones et al., 2014) of the protein kinome of the bloodstream form (BSF) of T. brucei identified 24 putative cell cycle regulators as playing a key role in the cell cycle of the parasite in vitro. From these candidates, TbKKT10, TbMAPK6, TbULK, TbCAMK, TbAEK1 and TbMAK kinases were potentially involved in cytokinesis and chosen for further analysis using a combination of an inducible RNAi silencing system, overexpression and kinase activity-dead mutants. Here, more detailed analysis reveals that TbMAK, TbCAMK and TbAEK1 are essential for cytokinesis, while TbKKT10, TbMAPK6, TbULK are essential for proliferation of the parasite, but do not play a role in cytokinesis. Depletion of TbCAMK or TbAEK1 led to inhibition of cell division, while depletion of TbMAK blocked the initiation of cytokinesis furrowing. Inducible overexpression of TbMAK6myc (but not TbAEK16myc or TbCAMK6myc) was lethal due to defective cytokinesis. Catalytically inactive kinases were generated by altering the ATP binding site, replacing the invariant lysine with methionine. Overexpression of catalytically inactive TbMAK(K33M)6myc abrogated the deleterious effects of overexpressing wild type TbMAK6myc, arguing that excess TbMAK activity is toxic to the cell and that expression of TbMAK is tightly regulated in wild type cells. Overexpression of catalytically inactive TbCAMK6myc or TbAEK16myc had no effect on cell proliferation. Moreover, analysis of immunoprecipitated TbMAK revealed that the kinase phosphorylates the generic kinase substrates, myelin basic protein and histone H1, but not α- or β-casein and is capable of autophosphorylating. Immunoprecipitated TbCAMK was able to autophosphorylate and phosphorylate myelin basic protein, α- or β-casein and histone H1. Additionally, preliminary mass spectrometry of TbMAK12myc immunoprecipitates indicate that TbMAK interacts with, and may potentially phosphorylate, various cytoskeletal proteins, thereby suggesting a putative mode of action for this kinase." @default.
• W3000230855 created "2020-01-23" @default.
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• W3000230855 date "2019-01-01" @default.
• W3000230855 modified "2023-09-28" @default.
• W3000230855 title "Characterisation of three essential protein kinases in Trypanosoma brucei reveals they are required for cytokinesis" @default.
• W3000230855 hasPublicationYear "2019" @default.
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