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    Donald John Tipper PhD

    TitleProfessor Emeritus
    InstitutionUniversity of Massachusetts Medical School
    DepartmentMicrobiology and Physiological Systems
    AddressUniversity of Massachusetts Medical School
    55 Lake Avenue North, S6-228
    Worcester MA 01655
    Phone508-856-2308
      Other Positions
      InstitutionUMMS - Programs, Centers and Institutes
      DepartmentBacterial Genetics and Pathogenesis

        Overview 
        Narrative

        Academic Background

        Ph. D. (1959) University of Birmingham (UK)

        Yeast Molecular Genetics

        The relationship between prion protein sequence and disease. Use of yeast as a model system for analysis of determinants of their transmembrane topology.

        Photo: Donald J. TipperMy laboratory uses yeast for the molecular genetic analysis of determinants of transmembrane (TM) protein topology. Both prion diseases and far more prevalent diseases such as Alzheimer's and cystic fibrosis result from errors in folding, membrane insertion, localization or processing of TM proteins. Although the topogenic signals that determine the topology of insertion are quite well understood (and have been extensively studied in yeast by my lab), the mechanisms for response to these signals are unknown. A long term goal is to characterize these mechanisms by the analysis of yeast mutants defective in responses to these signals. Our primary focus, however, is to use these techniques to analyze the relationship between mutations in the mammalian prion protein (PrP), membrane insertion and pathogenesis.

        Misfolded forms of PrP appear to be both the infectious agent of prion diseases and the primary cause of the neurotoxicity that leads to slowly lethal destruction of the brain. About 10% of human prion disease are familial, caused by mutations in the PrP gene. Recent studies show that, in at least one class of such mutants, neurotoxicity correlates with increased production of a normally rare transmembrane (TM) form of PrP, called PrPCtm, that may be the actual toxic form in all prion disease. We have shown that yeast is an efficient system for analysis of the relationship between pathogenic PrP mutations and TM topology. Using PrP as a model, we are collaborating in analysis of a previously unidentified component of the mammalian protein translocation apparatus that helps to control the topology of insertion of PrP and, presumably, other translocated proteins.



        Rotation Projects

        Rotation Projects

        1. Determine the mechanism of PrPCtm production by constructing PrP mutants with N-terminal glycosylation sites and analyzing their modification in yeast and in vitro.


        2. Test the role of PrPCtm in prion pathology by determining the effects of changing the charged topogenic signals in PrP on transmembrane insertion and pathogenicity.


        3. Isolate new pio mutants and determine their effects on normal yeast TM proteins.


        Bibliographic 
        selected publications
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        1. Campellone KG, Brady MJ, Alamares JG, Rowe DC, Skehan BM, Tipper DJ, Leong JM. Enterohaemorrhagic Escherichia coli Tir requires a C-terminal 12-residue peptide to initiate EspF-mediated actin assembly and harbours N-terminal sequences that influence pedestal length. Cell Microbiol. 2006 Sep; 8(9):1488-503.
          View in: PubMed
        2. Biswas S, Langeveld JP, Tipper D, Lu S. Intracellular accumulation of a 46 kDa species of mouse prion protein as a result of loss of glycosylation in cultured mammalian cells. Biochem Biophys Res Commun. 2006 Oct 13; 349(1):153-61.
          View in: PubMed
        3. Campellone KG, Rankin S, Pawson T, Kirschner MW, Tipper DJ, Leong JM. Clustering of Nck by a 12-residue Tir phosphopeptide is sufficient to trigger localized actin assembly. J Cell Biol. 2004 Feb 2; 164(3):407-16.
          View in: PubMed
        4. Tipper DJ, Harley CA. Yeast genes controlling responses to topogenic signals in a model transmembrane protein. Mol Biol Cell. 2002 Apr; 13(4):1158-74.
          View in: PubMed
        5. Campellone KG, Giese A, Tipper DJ, Leong JM. A tyrosine-phosphorylated 12-amino-acid sequence of enteropathogenic Escherichia coli Tir binds the host adaptor protein Nck and is required for Nck localization to actin pedestals. Mol Microbiol. 2002 Mar; 43(5):1227-41.
          View in: PubMed
        6. Breinig F, Tipper DJ, Schmitt MJ. Kre1p, the plasma membrane receptor for the yeast K1 viral toxin. Cell. 2002 Feb 8; 108(3):395-405.
          View in: PubMed
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