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Biochem Biophys Res Commun. 2008 Apr 18;368(4):875-81. doi: 10.1016/j.bbrc.2008.01.172. Epub 2008 Feb 12.

Normal cellular prion protein with a methionine at position 129 has a more exposed helix 1 and is more prone to aggregate.

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1
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic Research Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

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.

PMID:
18275852
DOI:
10.1016/j.bbrc.2008.01.172
[Indexed for MEDLINE]
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