2D IR OF AMYLOID PEPTIDES AND FIBRIL GROWTH

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病和其他几种流行的神经退行性疾病的特点是蛋白质错误折叠和聚集成由平行的β-折叠组成的纤维。纤维蛋白或前纤维低聚中间体似乎具有神经毒性特性，导致神经元退化和死亡。最近提出的A(β)原纤维的结构之间存在着显著的差异，对A(β)的前纤维中间体的结构知之甚少。显然，需要新的方法和新类型的数据。更好地了解这些病理结构是如何形成的，是理解它们形成的原因以及开发针对这些疾病的治疗干预措施的关键。因此，我们的目标是 1.测试、验证或改进成熟的A(β)40原纤维的结构模型。 2.表征A(β)40前纤维中间体的结构和神经毒性的发展。 与人们从最近发表的文献中得出的印象相反，在阿尔茨海默病中积累的淀粉样纤维的分子结构尚未完全阐明。 由于几个原因，淀粉样蛋白纤维非常适合应用2D-IR来确定蛋白质结构。首先，纤维是由40个残基的多肽链组成的，这些多肽链很容易用特定部位的同位素标记来合成。第二，原纤维中的多肽具有非常规则的二级结构。这有助于并简化了我们对2D-IR光谱的解释。第三，β-折叠可能比α-螺旋显示出更强烈、更清晰的峰，因为β-折叠中的酰胺跃迁偶极子比它们在α-螺旋中的排列更有利。此外，当纸张的链在对准时，平行测试页中的标签被强烈耦合。这导致了在α-螺旋中不会发生的链间耦合。第四，淀粉样蛋白是一种病理物质，其结构具有巨大的生物医学价值。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer's disease and several other prevalent neurodegenerative diseases are characterized by the misfolding and aggregation of proteins into fibrils composed of parallel beta-sheets. Either the fibrillar proteins or prefibrillar oligomeric intermediate forms appear to have neurotoxic properties that result in neuronal degeneration and death. There are significant discrepancies between recently proposed structures for the A(beta) fibril, and little is known about the structure of prefibrillar intermediate forms of A(beta). It is clear that new approaches and new kinds of data are needed. A better understanding of how these pathological structures form is key to understanding why they form, and to developing therapeutic interventions for these diseases. Therefore, we aim to 1. Test, verify, or refine structural models of the mature A(beta)40 fibril. 2. Characterize the development of structure and neurotoxicity in prefibrillar intermediate forms of A(beta)40. Contrary to the impression one might derive from recently published literature, the molecular structure of amyloid fibrils that accumulate in Alzheimer's disease has not been fully elucidated. For several reasons, amyloid fibrils are ideally suitable for the application of 2D-IR to the determination of protein structure. First the fibrils are composed of polypeptide strands of 40 residues that are readily synthesized with site-specific isotopic labels. Second, polypeptides within a fibril assume extremely regular secondary structure. This helps and simplifies our interpretation of 2D-IR spectra. Third, beta-sheets are likely to exhibit more intense and even better defined peaks than alpha-helices because the amide transition dipoles in a beta-sheet are more favorably aligned than they are in an alpha-helix. Also, labels in a parallel beta-sheet are strongly coupled when the strands of the sheet are in register. This gives rise to inter-strand coupling that would not occur in an alpha-helix. Fourth, amyloid represents a pathological material whose structure is of tremendous biomedical interest.