Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate.
The human prion gene, PRNP, has two allelic forms that encode either a methionine or valine at codon 129. This polymorphism strongly influences the pathogenesis of prion disease. However, the underlying mechanism remains unclear. We compared the conformation between wild-type human prion protein (rPrP(C)) with either a valine or methionine at position 129, using a panel of monoclonal antibodies that are specific for epitopes along the entire protein. We found that rPrP(C(129M)) has a more exposed helix 1 region compared to rPrP(C(129V)). Helix 1 is important in the aggregation process. Accordingly, rPrP(C(129M)) aggregates at a faster rate and forms more aggregate than rPrP(C(129V)). In addition, by using a rPrP with a pathogenic mutation of five additional octapeptide repeat insertions, rPrP((129M)/10OR), as "seeds", we showed that rPrP((129M)/10OR) promotes the aggregation of rPrP(C(129M)) more efficiently than rPrP(C(129V)). These findings provide a possible mechanism underlying the influence of residue 129 on human prion disease.
Pham
Nancy
N
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Research Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Yin
Shaoman
S
Yu
Shuiliang
S
Wong
Poki
P
Kang
Shin-Chung
SC
Li
Chaoyang
C
Sy
Man-Sun
MS
D000595:Amino Acid Sequence; D000939:Epitopes; D006801:Humans; D008715:Methionine; D000072002:Prion Proteins; D011328:Prions / Q000737:chemistry* / Q000235:genetics*; D011487:Protein Conformation; D020836:Protein Structure, Quaternary
D000939:Epitopes; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D008715:Methionine