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

Nancy Pham, Shaoman Yin, Shuiliang Yu, Poki Wong, Shin Chung Kang, Chaoyang Li, Man Sun Sy

Research output: Contribution to journalArticle

13 Scopus citations

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 (rPrPC) 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 rPrPC(129M) has a more exposed helix 1 region compared to rPrPC(129V). Helix 1 is important in the aggregation process. Accordingly, rPrPC(129M) aggregates at a faster rate and forms more aggregate than rPrPC(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 rPrPC(129M) more efficiently than rPrPC(129V). These findings provide a possible mechanism underlying the influence of residue 129 on human prion disease.

Original languageEnglish (US)
Pages (from-to)875-881
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume368
Issue number4
DOIs
StatePublished - Apr 18 2008
Externally publishedYes

Keywords

  • Aggregation
  • Epitope
  • Polymorphism
  • Prion protein

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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