Role of the Highly Conserved Middle Region of Prion Protein (PrP) in PrP−Lipid Interaction

详细信息    查看全文

• 作者：Fei Wang ; Shaoman Yin ; Xinhe Wang ; Liang Zha ; Man-Sun Sy ; Jiyan Ma
• 刊名：Biochemistry
• 出版年：2010
• 出版时间：September 21, 2010
• 年：2010
• 卷：49
• 期：37
• 页码：8169-8176
• 全文大小：943K
• 年卷期：v.49,no.37(September 21, 2010)
• ISSN：1520-4995

文摘

Converting normal prion protein (PrP^C) to the pathogenic PrP^Sc isoform is central to prion disease. We previously showed that, in the presence of lipids, recombinant mouse PrP (rPrP) can be converted into the highly infectious conformation, suggesting a crucial role of lipid−rPrP interaction in PrP conversion. To understand the mechanism of lipid−rPrP interaction, we analyzed the ability of various rPrP mutants to bind anionic lipids and to gain lipid-induced proteinase K (PK) resistance. We found that the N-terminal positively charged region contributes to electrostatic rPrP−lipid binding but does not affect lipid-induced PK resistance. In contrast, the highly conserved middle region of PrP, consisting of a positively charged region and a hydrophobic domain, is essential for lipid-induced rPrP conversion. The hydrophobic domain deletion mutant significantly weakened the hydrophobic rPrP−lipid interaction and abolished the lipid-induced C-terminal PK resistance. The rPrP mutant without positive charges in the middle region reduced the amount of the lipid-induced PK-resistant rPrP form. Consistent with a critical role of the middle region in lipid-induced rPrP conversion, both disease-associated P105L and P102L mutations, localized between lysine residues in the positively charged region, significantly affected lipid-induced rPrP conversion. The hydrophobic domain-localized 129 polymorphism altered the strength of hydrophobic rPrP−lipid interaction. Collectively, our results suggest that the interaction between the middle region of PrP and lipids is essential for the formation of the PK-resistant conformation. Moreover, the influence of disease-associated PrP mutations and the 129 polymorphism on PrP−lipid interaction supports the relevance of PrP−lipid interaction to the pathogenesis of prion disease.