Pham Nancy, Yin Shaoman, Yu Shuiliang, Wong Poki, Kang Shin-Chung, Li Chaoyang, Sy Man-Sun
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Research Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Biochem Biophys Res Commun. 2008 Apr 18;368(4):875-81. doi: 10.1016/j.bbrc.2008.01.172. Epub 2008 Feb 12.
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.
