A NOVEL MICROTUBULE-ASSOCIATED PROTEIN IN TRYPANOSOMES

Summary

Principal Investigator: KENT HILL
Abstract: DESCRIPTION (adapted from application abstract): African trypanosomes are protozoan parasites that cause African trypanosomiasis, a deadly disease with devastating health and economic consequences. The long-term goal of the proposed research is to advance our understanding of two vital components of the cellular architecture of these pathogens: the microtubule cytoskeleton, and the flagellar pocket, a specialized organelle that plays a critical role in host-parasite communication. Both of these structures are required for parasite survival in their mammalian host and insect vector, and are considered to be prime targets for therapeutic intervention in trypanosomiasis. We have shown that a protein called TLTF is localized to the cytoplasmic face of the anterior flagellar pocket membrane in trypanosome protein extracts and a related human protein associates with microtubules in mammalian cells. The first two aims of the proposed research are to utilize combined in vivo and in vitro microtubule binding assays to determine whether these two proteins are bona fide microtubule-binding proteins, and to determine whether or not microtubules contribute to targeting of TLTF in trypanosomes. Another aim of this research is to use biochemical and molecular biological approaches to determine whether the relationship between two anti- TLTF cross-reactive proteins that are present in insect-form trypanosomes. Expression of one of these proteins exhibits dramatic developmental regulation, suggesting that this protein has developmental stage-specific functions. Analysis of point mutations in the TLTF targeting domain suggests that specific protein-protein interactions at the flagellar pocket are important for proper targeting of TLTF. Hence, another aim of this research is to use co-immunoprecipitation and affinity capture resins to determine whether TLTF interacts with other trypanosomal proteins, i.e, whether some TLTF `binding partners` may be components of the flagellar pocket. In addition to contribution to our understanding of the cell biology of a medically important pathogen, the closely related properties of TLTF and a previously uncharacterized human protein make it likely that findings from these studies will have broad biological relevance in other systems.
Funding Period: 2001-07-01 - 2003-06-30
more information: NIH RePORT

Top Publications

  1. pmc Epidemiologic inference from the distribution of tuberculosis cases in households in Lima, Peru
    Ellen Brooks-Pollock
    Department of Epidemiology, Harvard School of Public Health, Brigham and Women s Hospital, Massachusetts General Hospital, Boston, USA
    J Infect Dis 203:1582-9. 2011
  2. ncbi Expanding the role of the dynein regulatory complex to non-axonemal functions: association of GAS11 with the Golgi apparatus
    Jessica R Colantonio
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA
    Traffic 7:538-48. 2006
  3. ncbi Direct interaction of Gas11 with microtubules: implications for the dynein regulatory complex
    Janine M Bekker
    Department of Physiological Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA
    Cell Motil Cytoskeleton 64:461-73. 2007

Scientific Experts

  • Ellen Brooks-Pollock
  • Janine M Bekker
  • Jessica R Colantonio
  • Rachelle H Crosbie
  • Kent L Hill
  • Andrew D Stephens
  • W Thomas Clarke
  • Stephen J King
  • Sarah J Kim
  • Kari M Morrissey

Detail Information

Publications3

  1. pmc Epidemiologic inference from the distribution of tuberculosis cases in households in Lima, Peru
    Ellen Brooks-Pollock
    Department of Epidemiology, Harvard School of Public Health, Brigham and Women s Hospital, Massachusetts General Hospital, Boston, USA
    J Infect Dis 203:1582-9. 2011
    ..Tuberculosis (TB) often occurs among household contacts of people with active TB. It is unclear whether clustering of cases represents household transmission or shared household risk factors for TB...
  2. ncbi Expanding the role of the dynein regulatory complex to non-axonemal functions: association of GAS11 with the Golgi apparatus
    Jessica R Colantonio
    Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA
    Traffic 7:538-48. 2006
    ..J Cell Biol 2003;162:47-57) and our findings suggest that components of this axonemal dynein regulatory system have been adapted in mammalian cells to participate in non-axonemal functions...
  3. ncbi Direct interaction of Gas11 with microtubules: implications for the dynein regulatory complex
    Janine M Bekker
    Department of Physiological Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA
    Cell Motil Cytoskeleton 64:461-73. 2007
    ..IMAD is able to function in either a cis- or trans-orientation with GMAD. The discovery that Gas11 provides a direct linkage to microtubules provides new mechanistic insight into the structural features of the dynein-regulatory complex...