Oligomeric structure and membrane disruption by an amyloid peptide from the mammalian prion protein

纤维状的错误折叠或聚集的蛋白质堆积是几种人类疾病的特征，包括淀粉样蛋白疾病，如II型糖尿病和阿尔茨海默病，以及海绵状脑病(Pron病)。这些疾病与不同蛋白质的错误折叠有关，并表现出不同的感染性机制，然而越来越多的证据表明错误折叠的蛋白质的细胞毒性的共同机制。具体地说，有人提出细胞死亡是由小的蛋白质聚集体引起的。最近的研究表明，这些有毒聚集体能够通过破坏细胞膜直接杀死细胞；可能是通过在质膜上形成通道或孔洞，或者只是通过诱导细胞内容物泄漏，从而导致细胞死亡和疾病状态的进展。为了揭示淀粉样蛋白毒性的这种常见机制，我们将表征哺乳动物蛋白(PrP)的一个神经毒性片段的分子结构和膜结合行为。除了形成淀粉样纤维外，PrP(106-126)还被证明可以形成小的神经毒性聚集体，并破坏细胞膜，使其成为我们研究的合适模型。利用固体核磁共振技术，我们将确定该多肽形成的毒性聚集体的分子结构，并确定PrP(106-126)与模型细胞膜的相互作用。具体来说，我们会：

The accumulation of misfolded or aggregated protein in a fibrillar form is characteristic of several human diseases including amyloid diseases, such as type II diabetes and Alzheimer's disease, as well as spongiform encephalopathies (prion diseases). These diseases are related to the misfolding of different proteins, and exhibit different mechanisms for infectivity, however growing evidence points to a common mechanism for the cytotoxicity of the misfolded proteins. Specifically, it has been proposed that cell death is caused by small protein aggregates. Recent studies have indicated that these toxic aggregates are able to directly kill cells by disrupting their membranes; possibly through formation of channels or holes in the plasma membrane, or simply by inducing leakage of cell contents, and that this leads to cell death and progression of the disease state. In order to unravel this common mechanism for amyloid protein toxicity, we will characterize the molecular structure and membrane-binding behaviour of a neurotoxic fragment of the mammalian prion protein (PrP). In addition to forming amyloid fibrils, PrP(106-126) has been shown to form small, neurotoxic aggregates and to disrupt membranes, making it a suitable model for our studies. Using solid state nuclear magnetic resonance (NMR), we will determine the molecular structure of the toxic aggregates formed by this peptide, and define the interactions of PrP(106-126) with model cell membranes. Specifically, we will: