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Theoretical Modeling of Molecular Mechanisms, Time Scales and Strains in Prion Diseases

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Final addendum 15 Jun 2006-14 Dec 2007

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We have obtained significant results modeling 1 the structure of the minimal infectious prion oligomer as a domain swapped beta helical trimer 2 metal binding to the prion protein showing results consistent with measured affinities and suggesting a detailed molecular role for the protection of the normal prion form against conversion to the infectious scrapies form when copper is bound to a particular site 3 kinetics of yeast prion aggregation in vitro illustrating the role of fission 4 kinetic analysis of transgenic mice time course data for anchorless cellular prions, indicating a that the membrane is necessary for exponential growth of infectious aggregate, and b that the elongation rate of anchorless prions is likely more rapid than anchored ones. In the coming year we will explore the role of our domain swapped model for 1 understanding strains, 2 understanding a subset of point mutations known to induce disease for those who inherit them, 3 possible docking of octarepeats to the beta helical trimers and their role in prion conversion, 4 additional metal binding to the prion protein iron, sodium, and copper at H111, and 5 the role of the membrane in inducing exponential growth of infectivity.

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  • Medicine and Medical Research
  • Microbiology

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