Interdisciplinary Graduate Programs Symposium
2008 OSU Molecular Life Sciences
Interdisciplinary Graduate Programs Symposium
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Poster abstracts
Abstract:
ABSTRACT
The interaction between prion protein (PrP) and lipids has been implicated in the pathogenesis of prion disease. Previously, we reported that the binding of recombinant PrP (rPrP) to anionic phospholipids results in a Proteinase K (PK)-resistant rPrP form that is similar to the pathogenic PrPSc isoform. To determine the relevance of rPrP-lipid interaction to prion biology, we characterized rPrP-lipid interaction using rPrP with pathogenic mutations and factors known to alter PrPSc propagation or stability. We found that, besides phospholipids, arachidonic acid also supports the generation of PK-resistant rPrP. In addition, lipid oxidation, metal ions and RNA affect lipid-induced rPrP conversion in a manner similar to their effects on PrPSc. Moreover, the lipid induced rPrP conversion requires both hydrophobic rPrP-lipid interaction and the localization of anionic charges on the surface of lipid vesicles, suggesting the involvement of highly conserved middle region of PrP that consists of a cluster of positively charged lysine residues followed by a hydrophobic domain. This notion is supported by our results that the middle region localized P105L mutation and the 129 polymorphism alter rPrP-lipid interaction. A significantly reduced lipid binding ability was observed with disease-associated P105L mutant. In contrast, the lipid binding capability of rPrP with either 129 valine or 129 methionine is comparable, yet only 129 valine is extracted from rPrP-lipid complex with an alkaline buffer, suggesting an alteration in the strength of hydrophobic interaction. Our findings highlight the specificity of PrP-lipid interaction and suggest a role of PrP-lipid interaction in pathogenesis of prion disease and in the biology of PrP.
Keywords: PrP, PrP-lipid interaction, Prion biology
