2D IR OF AMYLOID PEPTIDES AND FIBRIL GROWTH

淀粉样肽和纤维生长的二维红外图

• 批准号: 8169541
• 负责人: Paul H Axelsen
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169541
• 关键词: Alzheimer' s Disease; Amides; Amyloid; Amyloid Fibrils; Cessation of life; Computer Retrieval of Information on Scientific Projects Database; Coupled; Coupling; Data; Development; Disease; Exhibits; Funding; Grant; Growth; Institution; Label; Literature; Molecular Structure; Nerve Degeneration; Neurodegenerative Disorders; Property; Proteins; Publishing; Research; Research Personnel; Resources; Site; Source; Structural Models; Structure; Testing; Therapeutic Intervention; United States National Institutes of Health; alpha helix; amyloid peptide; beta pleated sheet; impression; interest; neurotoxic; neurotoxicity; novel strategies; polypeptide; protein aggregation; protein structure

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿尔茨海默病和其他几种流行的神经退行性疾病的特征是蛋白质错误折叠和聚集成由平行β折叠组成的原纤维。 纤维蛋白或前纤维寡聚中间体形式似乎具有导致神经元变性和死亡的神经毒性特性。 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) 前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类型。更好地了解这些病理结构是如何形成的，是了解它们形成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、验证或完善成熟 A(beta)40 原纤维的结构模型。 2. 表征 A(β)40 前原纤维中间形式的结构发展和神经毒性。 与人们从最近发表的文献中得到的印象相反，阿尔茨海默病中积累的淀粉样原纤维的分子结构尚未完全阐明。 由于多种原因，淀粉样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，这些多肽链很容易用位点特异性同位素标记合成。 其次，原纤维内的多肽呈现极其规则的二级结构。这有助于并简化我们对二维红外光谱的解释。 第三，β-折叠可能表现出比α-螺旋更强烈、甚至更好定义的峰，因为β-折叠中的酰胺过渡偶极子比它们在α-螺旋中更有利地排列。 此外，当片材的链对齐时，平行β片材中的标签会强烈耦合。 这会产生α螺旋中不会发生的链间偶联。 第四，淀粉样蛋白代表一种病理物质，其结构具有巨大的生物医学意义。