title: Structural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein.
abstract: A molecular understanding of the prion diseases requires delineation of the origin of misfolding of the prion protein (PrP). An understanding of how different disease-linked mutations affect the structure and dynamics of native monomeric PrP can provide a clue about how misfolding commences. In this study, hydrogen-deuterium exchange mass spectrometry was used to show that several disease-linked mutant variants, which are thermodynamically destabilized, share a common structural perturbation in their native states: helix 1 is destabilized to an extent that correlates well with the destabilization of the native protein. The mutant variants misfold and form oligomers faster than does the wild-type protein, at rates that increase exponentially with the extent to which helix 1 is destabilized in the native protein. It appears, therefore, that the loss of helix 1 structure marks the beginning of PrP misfolding and oligomerization.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru 560065 (India).
authors.forename: Jogender
authors.initials: J
authors.lastname: Singh
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru 560065 (India). jayant@ncbs.res.in.
authors.forename: Jayant B
authors.initials: JB
authors.lastname: Udgaonkar
mesh_terms: D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D009154:Mutation; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D011328:Prions
keywords: hydrogen-deuterium exchange; mass spectrometry; misfolding; pathogenic mutations; prion proteins