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: 8362569
• 负责人: Paul H Axelsen
• 金额: $ 2.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362569
• 关键词: Alzheimer' s Disease; Amides; Amyloid; Amyloid Fibrils; Cessation of life; Coupled; Coupling; Data; Development; Disease; Exhibits; Funding; Grant; Growth; Label; Laboratories; Literature; Molecular Structure; National Center for Research Resources; Nerve Degeneration; Neurodegenerative Disorders; Optics; Principal Investigator; Process; Property; Proteins; Publishing; Research; Research Infrastructure; Resources; Site; Source; Structural Models; Structure; Testing; Therapeutic Intervention; United States National Institutes of Health; alpha helix; amyloid peptide; beta pleated sheet; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 阿尔茨海默氏病和其他几种流行的神经退行性疾病的特征是将蛋白质折叠和聚集到由平行β片组成的原纤维中。 原纤维蛋白或原纤维寡聚中间形式似乎具有神经毒性特性，导致神经元变性和死亡。 A（beta）原纤维最近提出的结构之间存在显着差异，并且对A（beta）的前纤维中间形式的结构知之甚少。 显然，需要新的方法和新型数据。更好地理解这些病理结构是如何理解它们为什么形成的关键，并为这些疾病开发治疗干预措施。 因此，我们的目标是 1。测试，验证或完善成熟A（β）40纤维的结构模型。 2。表征在A（beta）40的前纤维中间形式中结构和神经毒性的发展。 与可能来自最近发表的文献的印象相反，在阿尔茨海默氏病中积累的淀粉样蛋白原纤维的分子结构尚未完全阐明。 由于几个原因，淀粉样蛋白原纤维非常适合将2D-IR应用于蛋白质结构的测定。 首先，原纤维由40个残基的多肽链组成，这些残基很容易与位点特异性同位素标签合成。 其次，原纤维内的多肽假定非常规则的二级结构。这有助于并简化我们对2D-IR光谱的解释。 第三，比阿尔图螺旋比α-螺旋更强烈，甚至更好地定义的峰可能会表现出更强烈的峰值，因为比β-螺旋中的酰胺过渡偶极子比在alpha-helix中更有利地排列。 同样，当板块的链在寄存器中时，平行β表中的标签会很强。 这会引起链间耦合，这不会发生在α-螺旋中。 第四，淀粉样蛋白代表了一种病理材料，其结构具有巨大的生物医学兴趣。