Pathogenic Mutations within the Disordered Palindromic Region of the Prion Protein Induce Structure Therein and Accelerate the Formation of Misfolded Oligomers

Abstract

Little is understood about how the intrinsically disordered N-terminal region (NTR) of the prion protein modulates its misfolding and aggregation, which lead to prion disease. In this study, two pathogenic mutations, G113V and A116V, in the palindromic region of the NTR are shown to have no effect on the structure, stability, or dynamics of native mouse prion protein (moPrP) but nevertheless accelerate misfolding and oligomerization. For wild-type moPrP, misfolding and oligomerization appear to occur concurrently, while for both mutant variants, oligomerization is shown to precede misfolding. Kinetic hydrogen–deuterium exchange–mass spectrometry experiments show that sequence segment 89–132 from the NTR becomes structured, albeit weakly, during the oligomerization of both mutant variants. Importantly, this structure formation occurs prior to structural conversion in the C-terminal domain and appears to be the reason that the formation of misfolded oligomers is accelerated by the pathogenic mutations.