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首页> 外文期刊>Journal of Molecular Biology >Vesicle permeabilization by purified soluble oligomers of prion protein: a comparative study of the interaction of oligomers and monomers with lipid membranes.
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Vesicle permeabilization by purified soluble oligomers of prion protein: a comparative study of the interaction of oligomers and monomers with lipid membranes.

机译：纯化的soluble病毒蛋白可溶性低聚物使囊泡通透性：寡聚物和单体与脂质膜相互作用的比较研究。

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The conversion of normal cellular prion protein (PrP) into its pathological isoform, scrapie PrP, may occur at the cell surface or, more probably, in late endosomes. The early events leading to the structural conversion of PrP appear to be related to the presence of more or less stable soluble oligomers, which might mediate neurotoxicity. In the current study, we investigate the interaction of alpha-rich PrP monomers and beta-rich size-exclusion-chromatography-purified PrP oligomers with lipid membranes. We compare their structural properties when associated with lipid bilayers and study their propensities to permeabilize the membrane at physiological pH. We also study the influence of the N-terminal flexible region (residues 24-103) by comparing full-length PrP(24-234) and N-terminally truncated PrP(104-234) oligomers. We showed that both 12-subunit oligomers cause an immediate and large increase in the permeability of the membrane, whereas equivalent amounts of monomeric forms cause no detectable leakage. Although the two monomeric PrP constructs undergo an alpha-to-beta conformational change when bound to the negatively charged membrane, only the full-length form of monomeric PrP has a weak fusogenic effect. Finally, the oligomers affect the integrity of the membrane differently from the monomers, independently of the presence of the N-terminal flexible domain. As for other forms of amyloidogenesis, a reasonable mechanism for the toxicity arising from PrP fibrillization must be associated with low-molecular-weight oligomeric intermediates, rather than with mature fibrils. Knowledge of the mechanism of action of these soluble oligomers would have a high impact on the development of novel therapeutic targets.
机译：正常细胞病毒蛋白（PrP）转化为其病理同种型瘙痒病PrP的转化可能发生在细胞表面，也可能发生在晚期内体中。导致PrP结构转化的早期事件似乎与或多或少稳定的可溶性低聚物的存在有关，这可能会介导神经毒性。在当前的研究中，我们调查了富含α的PrP单体和富含β的尺寸排阻色谱法纯化的PrP寡聚体与脂质膜的相互作用。我们比较了它们与脂质双层结合时的结构特性，并研究了它们在生理pH下能透化膜的倾向。我们还通过比较全长PrP（24-234）和N-末端截短的PrP（104-234）低聚物来研究N末端柔性区（残基24-103）的影响。我们表明，这两个12亚基低聚物均会导致膜通透性立即大量增加，而同等数量的单体形式则不会引起可检测的泄漏。尽管两个单体PrP构建体在与带负电荷的膜结合时会经历α-β构象变化，但只有全长形式的单体PrP具有弱的融合作用。最后，低聚物与单体不同地影响膜的完整性，独立于N末端柔性结构域的存在。至于其他形式的淀粉样蛋白生成，PrP原纤维化产生毒性的合理机制必须与低分子量低聚中间体相关，而不是与成熟原纤维相关。这些可溶性低聚物的作用机理的知识将对新型治疗靶标的开发产生重大影响。

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