2D IR OF AMYLOID PEPTIDES AND FIBRIL GROWTH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病和其他几种流行的神经退行性疾病的特征在于蛋白质错误折叠和聚集成由平行β-片层组成的原纤维。 无论是原纤维蛋白或前原纤维寡聚体中间形式似乎有神经毒性的性质，导致神经元变性和死亡。 最近提出的A（β）原纤维结构之间存在显着差异，并且对A（β）的预原纤维中间形式的结构知之甚少。 显然，需要新的方法和新的数据。更好地了解这些病理结构是如何形成的，是理解它们形成的关键，也是为这些疾病制定治疗干预措施的关键。 因此，我们的目标是 1.测试，验证，或完善成熟的A（β）40原纤维的结构模型。 2.表征A（β）40的前原纤维中间形式的结构和神经毒性的发展。 与最近发表的文献中的印象相反，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。 由于多种原因，淀粉样蛋白原纤维非常适合应用2D-IR测定蛋白质结构。 首先，原纤维由40个残基的多肽链组成，这些残基很容易用位点特异性同位素标记合成。 第二，原纤维内的多肽呈现极其规则的二级结构。这有助于简化我们对2D-IR光谱的解释。 第三，β-折叠可能比α-螺旋表现出更强烈甚至更好定义的峰，因为β-折叠中的酰胺过渡偶极比α-螺旋中的酰胺过渡偶极更有利地对齐。 此外，当片的链对齐时，平行β-片中的标记强烈偶联。 这引起了在α-螺旋中不会发生的链间偶联。 第四，淀粉样蛋白是一种病理材料，其结构具有巨大的生物医学意义。

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.