Copper(II) ions potently inhibit purified PrPres amplification

被引:41
作者
Orem, NR
Geoghegan, JC
Deleault, NR
Kascsak, R
Supattapone, S
机构
[1] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA
[2] Inst Basic Res Dev Disabil, Staten Isl, NY USA
关键词
copper; manganese; metals; prion; PrP; zinc;
D O I
10.1111/j.1471-4159.2006.03650.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The structural conversion of a host protein, PrPC, into a protease-resistant isoform, PrPres, is the central event in the pathogenesis of infectious prion diseases. Purification of native PrPC molecules from hamster brain by either cation exchange or immobilized chelator chromatographic resins yielded preparations that supported efficient amplification of scrapie-induced PrPres in vitro. Using these purified preparations, we determined that in vitro PrPres amplification was inhibited by CuCl2 and ZnCl2 at IC50 concentrations of similar to 400 nM and 10 mu M, respectively. In contrast, 100 mu M MnCl2 did not directly inhibit PrPres amplification or block Cu2+-mediated inhibition. Additionally, the inhibition of PrPres amplification by Cu2+ ions could be reversed by addition of either neocuproine or imidazole. Cu2+ inhibited PrPres amplification in both the presence and absence of stimulatory polyanion molecules. These biochemical findings support the hypothesis that Cu2+ ions might regulate the pathogenesis of prion diseases in vivo.
引用
收藏
页码:1409 / 1415
页数:7
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