PROTEIN PHOSPHORYLATION IN TRYPANOSOMES
Principal Investigator: Marilyn Parsons
Abstract: The protozoan parasite Jrypanosoma brucei is the causative agent of African sleeping sickness, a disease that is invariably fatal without treatment. T. brucei has served as a model system for the study of the related trypanosomatid pathogens Trypanosoma cruzi and Leishmania spp., and the three together infect over 20 million people worldwide. Leishmania has been a significant pathogen affecting American military personnel in the Middle East. The absence of vaccines and the toxic nature of drugs that combat these diseases, particularly sleeping sickness, make research into new drug and vaccine targets imperative. With the release of the genome sequences of all three trypanosomatids, we now face important decisions as to which of many targets to pursue. We have chosen to examine protein kinases and phosphatases since they are likely to be of major biological significance. Having identified all of the protein kinases in the genome through informatic studies, we will now identify all of the protein phosphatases. We also will examine the pattern of expression of protein kinases and phosphatases at the mRNA level. We are particularly interested identifying those molecules whose expression peaks in actively cycling cells in the bloodstream (human- infective) stage and those that may function as receptor kinases. We plan to pursue in more depth those molecules whose human homologues have served as drug targets for chronic diseases, including MAP kinase kinases and protein tyrosine phosphatases. Function will be approached through localization studies and RNAi knockdowns, as well as analysis of potential substrates. Together these studies will signficantly expand our knowledge of the network of signaling interactions in trypanosomes, with the goal of identifying new drug and vaccine targets.
Funding Period: ----------------1992 - ---------------2012-
more information: NIH RePORT
- Characterization of protein kinase CK2 from Trypanosoma bruceiBryan C Jensen
Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98108 5219, USA
Mol Biochem Parasitol 151:28-40. 2007..Studies of the enzymatic activity of the T. brucei CK2s show that both the affinity for GTP and stimulation by polyamines have been lost and only the features of heparin inhibition and stimulation by polybasic peptides are conserved...
- Widespread variation in transcript abundance within and across developmental stages of Trypanosoma bruceiBryan C Jensen
Seattle Biomedical Research Institute, 307 Westlake Ave North, Seattle, WA 98109, USA
BMC Genomics 10:482. 2009..Trypanosomatids represent a unique case in eukaryotes in that they transcribe protein-coding genes as large polycistronic units, and rarely regulate gene expression at the level of transcription initiation...
- The Trypanosoma brucei life cycle switch TbPTP1 is structurally conserved and dephosphorylates the nucleolar protein NOPP44/46Seemay Chou
Department of Molecular and Cell Biology and QB3 Institute, University of California, Berkeley, California 94720 3200, USA
J Biol Chem 285:22075-81. 2010..The structure reveals surfaces that may mediate substrate specificity and affords a template for the design of selective inhibitors to interfere with T. brucei transmission...
- Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage Trypanosoma bruceiChristal Worthen
Seattle Biomedical Research Institute, Seattle, Washington, USA
PLoS Negl Trop Dis 4:e678. 2010..New drugs that kill the causative agents, subspecies of Trypanosoma brucei, are therefore urgently needed. Little is known about the cellular mechanisms that lead to death of the pathogenic bloodstream stage...
- A novel protein kinase localized to lipid droplets is required for droplet biogenesis in trypanosomesJohn A Flaspohler
Seattle Biomedical Research Institute, WA 98109, USA
Eukaryot Cell 9:1702-10. 2010..Thus, LDK is required for the biogenesis or maintenance of lipid droplets and is one of the few protein kinases specifically and predominantly associated with an intracellular organelle...
- Trypanosoma brucei: Two mitogen activated protein kinase kinases are dispensable for growth and virulence of the bloodstream formBryan C Jensen
Seattle Biomedical Research Institute, 307 Westlake Ave N, Seattle, WA 98109, USA
Exp Parasitol 128:250-5. 2011..Bloodstream forms lacking MKK1 showed decreased growth at 39°C as compared to the parental line. However, unlike its Leishmania orthologue, T. brucei MKK1 does not appear to play a significant role in flagellar biogenesis...