title: Dynamic equilibria between monomeric and oligomeric misfolded states of the mammalian prion protein measured by 19F NMR.
abstract: The assembly of misfolded proteins is a critical step in the pathogenesis of amyloid and prion diseases, although the molecular mechanisms underlying this phenomenon are not completely understood. Here, we use (19)F NMR spectroscopy to examine the thermodynamic driving forces surrounding formation of β-sheet-rich oligomers early in the misfolding and aggregation pathway of the mammalian prion protein. We show that initial assembly of a small octameric intermediate is entropically driven, while further assembly to putative prefibrillar aggregates is driven by a favorable change in enthalpy. Kinetic data suggest that formation of the β-octamer represents a rate-limiting step in the assembly of prion aggregates. A disease-related mutation (F198S) known to destabilize the native state of PrP was also found to stabilize the β-octamer, suggesting that it can influence susceptibility to prion disease through two distinct mechanisms. This study provides new insight into the misfolding pathway leading to critical oligomers of the prion protein and suggests a physical basis for increased assembly of the F198S mutant.
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario, Canada M5S 3H6.
authors.forename: Sacha Thierry
authors.initials: ST
authors.lastname: Larda
authors.forename: Karen
authors.initials: K
authors.lastname: Simonetti
authors.forename: M Sameer
authors.initials: MS
authors.lastname: Al-Abdul-Wahid
authors.forename: Simon
authors.initials: S
authors.lastname: Sharpe
authors.forename: R Scott
authors.initials: RS
authors.lastname: Prosser
mesh_terms: D000818:Animals; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D011328:Prions / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D013816:Thermodynamics
chemical_list: D011328:Prions; D005461:Fluorine