Structural Effects of Multiple Pathogenic Mutations Suggest a Model for the Initiation of Misfolding of the Prion Protein

Abstract

Am olecular understanding of the prion diseases requires delineation of the origin of misfolding of the prion protein (PrP). An understanding of howd ifferent diseaselinked mutations affect the structure and dynamics of native monomeric PrP can provideaclue about howm isfolding commences.Inthis study,hydrogen-deuterium exchange mass spectrometry was used to showt hat several disease-linked mutant variants,w hicha re thermodynamically destabilized, share ac ommon structural perturbation in their native states: helix 1isdestabilizedtoane xtent 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 1i sd estabilizedi nt he native protein. It appears, therefore,that the loss of helix 1structure marks the beginning of PrP misfolding and oligomerization.

The G126V Mutation in the Mouse Prion Protein Hinders Nucleation-Dependent Fibril Formation by Slowing Initial Fibril Growth and by Increasing the Critical Concentration

“…A GdnHCl-induced equilibrium unfolding study indicated that G126V and wt moPrP had similar stabilities (Figure S1b). Hence, it appears that, similar to several other pathogenic mutations in the unstructured NTR, the G126V mutation did not affect the global stability of moPrP. ,, Thermodynamic stability is known to be a major modulator of the misfolding and aggregation propensities of the prion protein, ,, but not always. , It became important to study whether the G126V mutation had an effect on amyloid fibril formation, despite it not affecting the structure and stability of the protein.…”

“…The mouse prion protein (moPrP) is useful for studying the effects of disease-linked mutations found in the human prion protein (huPrP). ,,− Prion protein sequences are highly conserved across all mammals, with moPrP and huPrP having ∼85% identical sequences. In the middle hydrophobic region (residues 105–130; mouse numbering), the level of sequence identity is even higher.…”

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

“…For both sets of mutant variants, the misfolding rate constants were normalized to a value of 1 for the misfolding rate constant of 10 and 100 μM wt moPrP. Asterisks denote data for disease‐linked mutant variants, which was taken from references Singh & Udgaonkar, 2015, 2016b.…”

Membrane composition and lipid to protein ratio modulate amyloid kinetics of yeast prion protein

“…4–6 In humans, a conformational change of the prion protein between its non-toxic PrP c and a toxic PrP sc form is believed to be responsible for the disease pathology. 7–9 PrP sc contains the significant beta sheet, which facilitates the formation of highly insoluble aggregates. 10,11 These aggregates are partially resistant to proteolytic digestion.…”