2004
DOI: 10.1074/jbc.m401754200
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Abstract: The human PrP gene (PRNP) has two common alleles that encode either methionine or valine at codon 129. This polymorphism modulates disease susceptibility and phenotype of human transmissible spongiform encyphalopathies, but the molecular mechanism by which these effects are mediated remains unclear. Here, we compared the misfolding pathway that leads to the formation of ␤-sheet-rich oligomeric isoforms of the methionine 129 variant of PrP to that of the valine 129 variant. We provide evidence for differences i… Show more

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Cited by 58 publications
(84 citation statements)
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References 53 publications
(58 reference statements)
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“…a, mouse rPrP-(23-230) was folded into Am-rPrP, the ␤-sheet-rich form (␤-rPrP), or ␣-rPrP and subjected to the annealing procedure for 15 min at 80°C in 1% Triton X-100 and 100 mM Tris-HCl (pH 7.5), followed by PK digestion (1:50 PK/rPrP ratio). In contrast to a previous study in which PK digestion was performed at pH 5.5 (56), in this study at pH 7.5, ␤-sheetrich rPrP did not show any notable PK-resistant core (lanes 6 and 7). b, shown are the time and temperature dependence of the annealing reaction.…”
Section: Resultscontrasting
confidence: 47%
“…a, mouse rPrP-(23-230) was folded into Am-rPrP, the ␤-sheet-rich form (␤-rPrP), or ␣-rPrP and subjected to the annealing procedure for 15 min at 80°C in 1% Triton X-100 and 100 mM Tris-HCl (pH 7.5), followed by PK digestion (1:50 PK/rPrP ratio). In contrast to a previous study in which PK digestion was performed at pH 5.5 (56), in this study at pH 7.5, ␤-sheetrich rPrP did not show any notable PK-resistant core (lanes 6 and 7). b, shown are the time and temperature dependence of the annealing reaction.…”
Section: Resultscontrasting
confidence: 47%
“…Furthermore, the codon 129 polymorphism regulates retro-translocation because in group II, Val 129 containing mutants have normal levels of CyPrP and retain their anti-Bax function, whereas Met 129 containing mutants have reduced CyPrP levels and partially or completely lose the anti-Bax function. Relative to Val 129 , the Met 129 increases the ability of PrP to fold with a higher ␤-sheet content and to oligomerize (Tahiri-Alaoui et al, 2004). Therefore, it is likely that codon 129 and familial mutations slightly alter the conformation of PrP, thus resulting in altered posttranslational trafficking.…”
Section: Discussionmentioning
confidence: 99%
“…The high frequency of heterozygous 129 genotype within historical populations implies balancing selection at the locus, similar mechanism which was proposed for contemporary worldwide population by Mead. On the basis of the worldwide high frequency of heterozygote M129V in moderns [22,23] an occurrence of a strong balancing selection pressure in favor resistant variants has been suggested. According to Mead, the high level of heterozygous genotype presence in moderns is probably associated with evolutionary selective pressure leading to gene diversity [22].…”
Section: Discussionmentioning
confidence: 99%