TitleStructural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein.
Publication TypeJournal Article
Year of Publication2015
AuthorsSingh J, Udgaonkar JB
JournalAngew Chem Int Ed Engl
Date Published2015 Jun 22

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.

Alternate JournalAngew. Chem. Int. Ed. Engl.
PubMed ID25959220