The Prion protein (PrP) is a membrane-tethered glycoprotein that plays a central role in a unique class of neurodegenerative diseases that affect humans and other mammals. Prion diseases have genetic and sporadic origins, but their infectious nature sets them apart from other neurodegenerative disorders. According to the "protein-only" hypothesis, misfolded PrP conformers (prions) are responsible for both spongiform degeneration of the brain and disease transmissibility. Thus, understanding PrP conformational dynamics is key to developing effective therapies. Classic studies showing the different susceptibility to prion disease in mammals have recently found support in structural and transgenic studies with PrP from susceptible (mouse, hamster) and resistant (rabbit, horse, dog) animals. These studies identify key residues in PrP that determine both PrP structure and its propensity to acquire a ß-structure conformation proposed to be neurotoxic.
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to be the most critical bements in the loop (S167%cause o-E168, Pf its abFig.1), aOility to slthoPtabugh SUilize m167 sEouseeemsJTblock oUr rSeveJrt PCrP coVnversiUon aFnd disease progression. PrP.21 S167 seems to be in close contact with F225 (another Acknowledgements exclusive substitution in the horse) in α3, providing a unique This work was funded by the NIH grant R01NS062787, mechanism for stabilizing the ß2-α2 loop and α3. Additionally, McGregor Foundation and the President’s Discretionary Fund the Y225F substitution (Y225V in rabbit) introduces a hydro-and Alliance BioSecure to W.Z., and the NIH grant DP2 phobic residue that has to be buried in a hydrophobic pocket, OD002721-01 to P.F.F.
- Drosophila models
- Prion diseases
- Prion protein
- Protein structure