朊病毒蛋白是错误一类错误折叠的蛋白,通常这些蛋白具有β折叠结构域,并能够形成淀粉纤维状蛋白聚集体。这种聚集体溶解性差,并可以诱导周围具有正确构象的朊蛋白转变成错误构象,使这种蛋白聚集体能够扩增,具有“传染性”。临床上,很多代谢疾病和神经退行性疾病与是由这种错误构象的蛋白引发的。近年的研究发现,在这些错误折叠的蛋白粒子中,有辅助因子的参与。但是辅助因子是否参与维持蛋白的错误构象以及是否有助于蛋白聚集体的扩增并不清楚。
本文中,研究者用含有辅助因子的蛋白聚集体与只含阮蛋白的蛋白聚集体作对比。证明了去除辅助因子的蛋白聚集体在体外不具有“传染性”,也不能诱导正确折叠的朊蛋白改变构象。研究者认为,朊蛋白辅助因子是组成传染性蛋白聚集体的基本成分,它在维持聚集体构象和诱导正确折叠蛋白的构象改变中起重要作用。
这一研究指出,辅助因子可能在一些神经退行性疾病的发生中扮演着重要角色,因此该研究有助于我们更好的理解这些疾病的发病机制。(生物谷 Bioon.com )
doi:10.1073/pnas.1206999109
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Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions
Nathan R. Deleault, Daniel J. Walsh, Justin R. Piro, Fei Wang, Xinhe Wang, Jiyan Ma, Judy R. Rees, and Surachai Supattapone
Prions containing misfolded prion protein (PrPSc) can be formed with cofactor molecules using the technique of serial protein misfolding cyclic amplification. However, it remains unknown whether cofactors materially participate in maintaining prion conformation and infectious properties. Here we show that withdrawal of cofactor molecules during serial propagation of purified recombinant prions caused adaptation of PrPSc structure accompanied by a reduction in specific infectivity of >105-fold, to undetectable levels, despite the ability of adapted “protein-only” PrPSc molecules to self-propagate in vitro. We also report that changing only the cofactor component of a minimal reaction substrate mixture during serial propagation induced major changes in the strain properties of an infectious recombinant prion. Moreover, propagation with only one functional cofactor (phosphatidylethanolamine) induced the conversion of three distinct strains into a single strain with unique infectious properties and PrPSc structure. Taken together, these results indicate that cofactor molecules can regulate the defining features of mammalian prions: PrPSc conformation, infectivity, and strain properties. These findings suggest that cofactor molecules likely are integral components of infectious prions.