The presence of valine at residue 129 in human prion protein accelerates amyloid formation

Abstract

The polymorphism at residue 129 of the human PRNP gene modulates disease susceptibility and the clinicopathological phenotypes in human transmissible spongiform encephalopathies. The molecular mechanisms by which the effect of this polymorphism are mediated remain unclear. It has been shown that the folding, dynamics and stability of the physiological, a-helix-rich form of recombinant PrP are not affected by codon 129 polymorphism. Consistent with this, we have recently shown that the kinetics of amyloid formation do not differ between protein containing methionine at codon 129 and valine at codon 129 when the reaction is initiated from the a-monomeric PrP C -like state. In contrast, we have shown that the misfolding pathway leading to the formation of b-sheet-rich, soluble oligomer was favoured by the presence of methionine, compared with valine, at position 129. In the present work, we examine the effect of this polymorphism on the kinetics of an alternative misfolding pathway, that of amyloid formation using partially folded PrP allelomorphs. We show that the valine 129 allelomorph forms amyloids with a considerably shorter lag phase than the methionine 129 allelomorph both under spontaneous conditions and when seeded with pre-formed amyloid fibres. Taken together, our studies demonstrate that the effect of the codon 129 polymorphism depends on the specific misfolding pathway and on the initial conformation of the protein. The inverse propensities of the two allelomorphs to misfold in vitro through the alternative oligomeric and amyloidogenic pathways could explain some aspects of prion diseases linked to this polymorphism such as age at onset and disease incubation time.

Probing Structural Differences in Prion Protein Isoforms by Tyrosine Nitration

“…Tyr128 is adjacent to Met129 and is hydrogen bonded to Asp178 in many of the hamster PrP C solution structures (72). Both Met129 and Asp178 are residues linked to human disease (73)(74)(75)(76)(77). The D178N mutation causes fatal familial insomnia if residue 129 is Met, and causes CreutzfeldtJakob disease if the variant Val129 is present.…”

Molecular Heterosis of Prion Protein β-Oligomers

“…Conversely, the amyloid pathway ( Fig. 1, pathway 4) is favored by the presence of a valine residue at position 129 (19). In both of these cases, however, the properties of mixtures of Met-129 and Val-129 were intermediate between those of the respective homogenous populations, shedding little light on the presumed behavior of PrP in heterozygous individuals.…”

NMR characterization of the pH 4 β-intermediate of the prion protein: the N-terminal half of the protein remains unstructured and retains a high degree of flexibility

“…Recent studies have shown that stability of the native α-helical PrP is unaffected by polymorphism at 129 (Met 129 or Val 129 ) [26]. However, the presence of valine at position 129 accelerates fibril formation at pH 7 [27], while conversely Met 129 favours the formation of the pH 4 soluble intermediate [28]. Interestingly, only individuals homozygous for methionine at 129 (Met/Met) have contracted variant CJD [29].…”