Curcumin binds to the α-helical intermediate and to the amyloid form of prion protein -: a new mechanism for the inhibition of PrPSc accumulation
Curcumin binds to the α-helical intermediate and to the amyloid form of prion protein -: a new mechanism for the inhibition of PrPSc accumulation
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DOI：
10.1111/j.1471-4159.2007.05105.x
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发表时间：
2008-03-01
影响因子：
4.7
通讯作者：
Jerala, Roman
中科院分区：
文献类型：
--
作者：
Hafner-Bratkovic, Iva;Gaspersic, Jernej;Jerala, Roman
朊病毒蛋白（PrP）的天然主要α-螺旋构象转化为β-链构象是传染性海绵状脑病如克-雅二氏病的特征。姜黄素，一个扩展的平面分子和膳食多酚，抑制体外转化的PrP和蛋白酶耐药的PrP在神经母细胞瘤细胞系的形成。姜黄素识别转化的PrP β-形式作为低聚物和原纤维，但不识别天然形式。姜黄素结合朊病毒原纤维的左手手性安排确定的圆二色性。我们发现，姜黄素标记的斑块的变异克雅氏病的情况下，和染色相同的结构作为抗体对朊蛋白的大脑部分。与硫磺素T相反，姜黄素还结合到在酸性pH下以1：1的化学计量存在的PrP的α-螺旋中间体。刚果红与姜黄素竞争结合α-中间体以及β-形式的PrP，但刚果红有毒，并且也结合天然形式的PrP。因此，我们表明，PrP的部分未折叠的结构中间体可以通过天然来源的无毒化合物靶向。
Conversion of the native, predominantly alpha-helical conformation of prion protein (PrP) into the beta-stranded conformation is characteristic for the transmissible spongiform encephalopathies such as Creutzfeld-Jakob disease. Curcumin, an extended planar molecule and a dietary polyphenol, inhibits in vitro conversion of PrP and formation of protease resistant PrP in neuroblastoma cell lines. Curcumin recognizes the converted beta-form of the PrP both as oligomers and fibrils but not the native form. Curcumin binds to the prion fibrils in the left-handed chiral arrangement as determined by circular dichroism. We show that curcumin labels the plaques of the brain sections of variant Creutzfeld-Jakob disease cases and stains the same structures as antibodies against the PrP. In contrast to thioflavin T, curcumin also binds to the alpha-helical intermediate of PrP present at acidic pH at stoichiometry of 1 : 1. Congo red competes with curcumin for binding to the alpha-intermediate as well as to the beta-form of PrP but is toxic and binds also to the native form of PrP. We therefore show that the partially unfolded structural intermediate of the PrP can be targeted by non-toxic compound of natural origin.