Structural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein.
|Title||Structural effects of multiple pathogenic mutations suggest a model for the initiation of misfolding of the prion protein.|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Singh J, Udgaonkar JB|
|Journal||Angew Chem Int Ed Engl|
|Date Published||2015 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 Journal||Angew. Chem. Int. Ed. Engl.|