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。 阿尔茨海默神经退行性疾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原纤维的结构模型。 2.表征A-β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的疾病还没有解决。 由于多种原因，淀粉样纤维是应用2D-IR-COSY测定蛋白质结构的理想样品。 首先，原纤维由容易用位点特异性同位素标记合成的多肽组成。 第二，已知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-COSY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-折叠中的过渡偶极子比α-螺旋中的过渡偶极子更好地彼此对齐。 此外，平行β-折叠中的标记彼此偶联，因为如果折叠的链对齐，则它们对齐。 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. Alzheimers 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 fibril. 2. Characterize the development of structure and neurotoxicity in prefibrillar intermediate forms of A-beta. Contrary to the impression one might derive from recently published literature, the molecular structure of amyloid fibrils that accumulate in Alzheimers disease has not been solved. For several reasons, amyloid fibrils are an ideal sample for the application of 2D-IR-COSY to the determination of protein structure. First, fibrils are composed of polypeptides that are readily synthesized with site-specific isotopic labels. Second, polypeptides within a fibril are known to assume extremely regular secondary structure. This aids and simplifies our interpretation of 2D-IR-COSY spectra. Third, beta-sheets are likely to exhibit more intense and even better defined peaks than alpha-helices because transition dipoles in a beta-sheet are better aligned to each other than they are in an alpha-helix. Also, labels in a parallel beta-sheet are coupled to each other because they are aligned if 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.