AB MONOMER STRUCTURE AND ASSEMBLY

AB 单体结构和组装

• 批准号: 7112187
• 负责人: Michael Thomas Bowers
• 金额: $ 25.74万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112187
• 关键词: Alzheimer' s disease; aminoacid; amyloid proteins; amyloidosis; chemical aggregate; chemical substitution; mass spectrometry; molecular assembly /self assembly; molecular dynamics; molecular pathology; neuropathology; oligopeptides; organic brain syndrome; protein binding; protein folding; protein sequence; protein structure function; temperature

The objective of this research is to understand, on a molecular level, the folding and assembly of Abeta-protein alloforms. Recent results indicate small, soluble oligomers of Abeta are responsible for initiating a pathological cascade resulting in Alzheimer's disease (AD). Abeta42 has been shown to be the primary neurotoxic agent even though Abeta40 is nearly 10 times more abundant. Single-point amino-acid substitutions at positions 22 and 23 in Abeta42 account for a variety of familial forms of AD. It is our hypothesis that Abeta monomers and small oligomers are important therapeutic targets and characterization of their structure and mechanisms of folding and assembly are critical research objectives. Here we propose to apply, for the first time, the powerful methods of ion mobility spectrometry coupled with mass spectrometry (IMS-MS) to the problem of Abeta folding and assembly. These methods provide accurate measures of monomer and oligomer cross sections and oligomer-size distributions. When coupled with high-level molecular dynamics modeling, monomeric structure with atomic detail is obtained. The method is ultrasensitive, routinely working with picomoles of sample or less. These methods can be readily extended to other neurological diseases like ALS and Parkinson's disease that share the misfolding/aggregation motif with AD. The specific aims of this research are (1) to structurally characterize Abeta monomers and to determine how these structures change with single-amino-acid substitution, oxidation or other simple sequence modification, (2) to structurally characterize Abeta monomer fragments and determine how these structures change with sequence length, single-amino-acid substitutions or other modifications, and (3) to measure oligomer-size distributions and oligomer structures for the early stages of assembly in Abeta and modified forms of Abeta40 and Abeta42.

本研究的目的是在分子水平上了解 Abeta 蛋白的折叠和组装 同种异体。最近的结果表明，小的、可溶性的 Abeta 寡聚物负责引发 导致阿尔茨海默病（AD）的病理级联反应。 Abeta42 已被证明是主要的 尽管 Abeta40 的含量高出近 10 倍，但它仍然是神经毒剂。单点氨基酸取代 Abeta42 中第 22 和 23 位的基因可以解释 AD 的多种家族形式。我们的假设是阿贝塔 单体和小寡聚物是重要的治疗靶点及其结构和表征 折叠和组装机制是关键的研究目标。在这里我们建议先申请 随着时间的推移，离子迁移谱与质谱 (IMS-MS) 相结合的强大方法 Abeta折叠和组装问题。这些方法提供了单体和低聚物的准确测量 横截面和低聚物尺寸分布。当与高级分子动力学建模相结合时， 获得具有原子细节的单体结构。该方法非常灵敏，通常与 样品的皮摩尔或更少。这些方法可以很容易地扩展到其他神经系统疾病，例如 ALS 和帕金森病与 AD 具有相同的错误折叠/聚集基序。 本研究的具体目标是 (1) 表征 Abeta 单体的结构并确定如何 这些结构通过单氨基酸取代、氧化或其他简单的序列修饰而改变， (2) 表征 Abeta 单体片段的结构并确定这些结构如何随 序列长度、单氨基酸取代或其他修饰，以及 (3) 测量寡聚体大小 Abeta 和 Abeta40 的修饰形式的早期组装阶段的分布和低聚物结构 阿贝塔42。