The Toxicity of Prion Protein Fragment PrP(106-126) is Not Mediated by Membrane Permeabilization as Shown by a M112W Substitution
The Toxicity of Prion Protein Fragment PrP(106-126) is Not Mediated by Membrane Permeabilization as Shown by a M112W Substitution
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DOI：
10.1021/bi900009d
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发表时间：
2009-05-19
期刊：
影响因子：
2.9
通讯作者：
Castanho, Miguel A. R. B.
中科院分区：
文献类型：
--
作者：
Henriques, Sonia Troeira;Pattenden, Leonard Keith;Castanho, Miguel A. R. B.
朊病毒疾病是由生理性朊病毒蛋白 (PrPC) 翻译后修饰为痒病亚型 (PrPsc) 引起的。 PrP(106-126) 片段在各种异常变异中保守，并显示出 PrPsc 致病特性。有人提出，PrP(106-126) 片段可能通过膜孔的形成发挥其毒性作用。我们之前的研究表明，PrP(106-126) 在生理条件下不与膜相互作用。在本研究中，通过用M112W取代修饰PrP(106-126)来增加PrP(106-126)对膜的亲和力，并进一步评估了孔的形成。然而，虽然肽在膜中表现出局部浓度增加，但这并没有导致膜透化的诱导，如荧光方法和表面等离子体共振所证实的。这些结果进一步支持这样的观点：PrP(106-126) 毒性不是肽-膜相互作用和孔形成的结果。
Prion diseases result from a post-translational modification of the physiological prion protein (PrPC) into a scrapie isoform (PrPsc). The PrP(106-126) fragment conserved among various abnormal variants and shows PrPsc pathogenic properties. It has been proposed that the PrP(106-126) fragment may exhibit its toxic effects through membrane pore formation. Our previous studies showed that PrP(106-126) does not interact with membranes under physiological conditions. In the present study, PrP(106-126) affinity for membranes was increased by modifying PrP(106-126) with a M112W substitution, and pore formation was further evaluated. However, while the peptide exhibited an increased local concentration in the membrane, this did not lead to the induction of membrane permeabilization, as verified by fluorescence methodologies and surface plasmon resonance. These results further support the idea that PrP(106-126) toxicity is not a consequence of peptide-membrane interaction and pore formation.