An unusual soluble beta-turn-rich conformation of prion is involved in fibril formation and toxic to neuronal cells.
An unusual soluble beta-turn-rich conformation of prion is involved in fibril formation and toxic to neuronal cells.
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DOI：
10.1016/j.bbrc.2004.12.172
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发表时间：
2005-03
影响因子：
3.1
通讯作者：
J. Kazlauskaitė;Anna Young;C. E. Gardner;J. Macpherson;C. Vénien-Bryan;T. Pinheiro
中科院分区：
文献类型：
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作者：
J. Kazlauskaitė;Anna Young;C. E. Gardner;J. Macpherson;C. Vénien-Bryan;T. Pinheiro
Prion疾病中的一个关键分子事件是PrP蛋白(PrP)从其正常细胞形式(PrPC)转变为疾病特异性形式(PrPSc)。从PrPC到PrPSc的转变涉及到一个主要的构象变化，导致无定形的蛋白质聚集体和纤维状淀粉样沉积，具有更多的β-Sheet结构。利用复性后的富含β片状的重组PrP(β-PrP)，我们研究了β-PrP在溶液中和与RAFT膜结合时的成膜作用。在低离子强度时，粗密的原纤维形成大的网络，与无定形聚集体共存。高离子强度会导致纤维不那么紧密，这些纤维以大片状的球形PrP颗粒聚集在一起，类似于PrPSc体外制剂中发现的弥漫聚集体。在这里，我们报告了在Pron纤化过程中发现的富含β转角的构象，这种构象对培养的神经细胞是有毒的。这是首次报道对神经细胞有毒性的蛋白原纤维形成过程中的中间体。我们认为，这种不寻常的富含β转角的PrP形式可能是PrPSc的前体，也是PrP致病机制中神经毒性分子的候选分子。
A key molecular event in prion diseases is the conversion of the prion protein (PrP) from its normal cellular form (PrPC) to the disease-specific form (PrPSc). The transition from PrPCto PrPScinvolves a major conformational change, resulting in amorphous protein aggregates and fibrillar amyloid deposits with increased β-sheet structure. Using recombinant PrP refolded into a β-sheet-rich form (β-PrP) we have studied the fibrillization of β-PrP both in solution and in association with raft membranes. In low ionic strength thick dense fibrils form large networks, which coexist with amorphous aggregates. High ionic strength results in less compact fibrils, that assemble in large sheets packed with globular PrP particles, resembling diffuse aggregates found in ex vivo preparations of PrPSc. Here we report on the finding of a β-turn-rich conformation involved in prion fibrillization that is toxic to neuronal cells in culture. This is the first account of an intermediate in prion fibril formation that is toxic to neuronal cells. We propose that this unusual β-turn-rich form of PrP may be a precursor of PrPScand a candidate for the neurotoxic molecule in prion pathogenesis.