Mutations of evolutionarily conserved aromatic residues suggest that misfolding of the mouse prion protein may commence in multiple ways

In this study, using hydrogen exchange and mass spectrometry, we found that the native state of the mouse prion protein is in equilibrium with multiple partially unfolded forms (PUFs) capable of initiating misfolding. Mutating three conserved aromatic residues destabilized the native state and reduced energy differences between the native state and two PUFs. Misfolding can initiate from these distinct PUFs, suggesting multiple pathways for misfolding. Mutant variants significantly increase the population of the PUFs, accelerating misfolding. This implies that the three aromatic residues may have evolved to impede misfolding. AbstractThe misfolding of the mammalian prion protein from its α-helix rich cellular isoform to its β-sheet rich infectious isoform is associated with several neurodegenerative diseases. The determination of the structural mechanism by which misfolding commences, still remains an unsolved problem. In the current study, native-state hydrogen exchange coupled w ith mass spectrometry has revealed that the N state of the mouse prion protein (moPrP) at pH 4 is in dynamic equilibrium with multiple partially unfolded forms (PUFs) capable of initiating misfolding. Mutation of three evolutionarily conserved aromatic residues, Tyr168, Phe174, and Tyr217 present at the interface of the β2-α2 loop and the C-terminal end of α3 in the structured C-terminal domain of moPrP significantly destabilize the native state (N) of the protein. They also reduce the free en...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research