title: Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate.
abstract: 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.
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Research Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Pham
authors.forename: Shaoman
authors.initials: S
authors.lastname: Yin
authors.forename: Shuiliang
authors.initials: S
authors.lastname: Yu
authors.forename: Poki
authors.initials: P
authors.lastname: Wong
authors.forename: Shin-Chung
authors.initials: SC
authors.lastname: Kang
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Li
authors.forename: Man-Sun
authors.initials: MS
authors.lastname: Sy
mesh_terms: 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
chemical_list: D000939:Epitopes; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D008715:Methionine