Multiple Substitutions of Methionine 129 in Human Prion Protein Reveal Its Importance in the Amyloid Fibrillation Pathway

Abstract

Background: A polymorphism in position 129 in the human prion protein modulates susceptibility to prion infection and disease phenotype. Results: Mutations to various amino acids highlights the importance of position 129 during amyloid fibrillation. Conclusion: Position 129 is a key site for early intermolecular interactions during fibrillation. Significance: Insight into early mechanisms of aggregation implicates a means to prevent fibrillation.

Is the prevalent human prion protein 129M/V mutation a living fossil from a Paleolithic panzootic superprion pandemic?

“…1) which suggest that prion replication is hampered in M129V carriers. 16 This impaired molecular conversion is reminiscent of the high kinetic barriers dissociation of the native tetramer shown for TTR T119M suppressor mutant carriers resistant for FAP. Our data hence suggest that elevated kinetic barriers for PrP conversion in M129V is a plausible molecular mechanism for heterozygote advantage.…”

“…16 The basis for selection of this site for mutagenesis was obvious from its strong genetic link to prion disease as discussed above. Our data was based on the in vitro behavior of PrP in solution and showed that position 129 was an important site for recruitment of PrP into the amyloid state.…”

Impact of methionine oxidation as an initial event on the pathway of human prion protein conversion

“…Similar to Ser, threonine increases the local polarity, but mimics the structural demands of MetO better than Ser. Since the replacement with isosteric valine did not induce any structural instability at this position, 30 all resulting effects should be attributed only to the polarity increase within the M129T mutant.…”

“…Previous studies reported that the unstructured N-terminal domain did not significantly influence the destabilization of the native PrP fold if induced by site-specific mutation or by oxidation. 19,25 Additionally, we designed two pseudosulfoxidation mutants to mimic methionine oxidation at selected, surface exposed Met residues, which should enable a site-specific investigation of the structural consequences of oxidation at solvent accessible methionines only. The strategy to provide a property of a chemical covalent modification by mutation against a suitable residue is well established to mimic phosphorylation and also sulfoxidation.…”

“…The consequences of further structural destabilization depend on the experimental conditions, including the formation of amorphous aggregates, of β-sheet enriched oligomers, or of amyloid fibrils, as well as β-cleavage. 16,17,19,[21][22][23][24] Another prominent relevance for destabilizing the native PrP fold was attributed by mutagenesis studies to polymorphic Met129 (M129V), 25 which modulates the risk and phenotype of prion diseases in humans. 26 We recently reported that both UV light and metal-induced oxidation significantly affect the structural integrity of recombinant PrP.…”