CONFORMATIONS OF ALZHEIMER PHF/TAU AND TAU PEPTIDES

阿尔茨海默病 PHF/TAU 和 TAU 肽的构象

• 批准号: 2706006
• 负责人: WARREN J GOUX
• 金额: $ 6.78万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2706006
• 关键词: Alzheimer's disease; aluminum; circular dichroism; conformation; membrane model; micelles; neurofibrillary tangles; nuclear magnetic resonance spectroscopy; paired helical filament; phosphorylation; protein structure function; tau proteins

Two hallmark lesions present in brains of Alzheimer's diseased patients are senile plaques (SP) and neurofibrillay tangles (NFT). The NFT are composed of paired helical filaments (PHF) single straight filaments (SSF) and their density in AD brain sections has been correlated with the severity of the disease. Although NFT are the most visible abnormal structures occurring in AD at the cellular level, their formation, persistence and eventual neurotoxicity is most likely elicited by more subtle abnormal metabolic changes, ultimately directed by the cell genome. It follows that an understanding to those factors responsible for initiation of their formation and, in the case of NFT, their insolubility and protease resistance might provide clues to the underlying etiology of AD. The central goal of this proposal is to investigate some of the factors which have been postulated to initiate PHF formation and to maintain its structure. Numerous biochemical and immunological studies over the last decade have shown that PHF is composed of the microtubule associated protein, tau (PHF-tau). One of the primary differences between normal tau and PHF- tau is that PHF-tau appears to be more highly phosphorylated by ser/thr- pro directed kinases. Since phosphorylated tau shows decreased binding to microtubules, a reasonable hypothesis for the PHF assembly is an initial phosphorylation of tau which in turn leads to self-association of the protein monomers into fibers. One of the goals of this proposal is to determine if phosphorylation can indeed induce conformational changes in peptides homologous to sequences of tau known to be of importance in microtubule binding. Recently it has been found that non-phosphorylated full length tau is able to form PHF-like filaments under physiological conditions when incubated in vitro in the presence of glycosaminoglycans such as heparin and heparin sulfate. Furthermore, single fillaments can be formed when an 18-amino acid peptide derived from the microtubule binding region of tau is incubated with heparin or poly-L-glutamic acid. Using biophysical methods we intend to study conformational changes in this peptide and homologous peptides brought about under fiber inducing conditions. This will address the hypothesis of whether a conformational change is a preliminary condition to fiber formation. A detailed model of any conformational changes will be derived from CD and NMR/distance geometry methods.

阿尔茨海默病患者大脑中存在两种标志性病变 是老年斑（SP）和神经原纤维缠结（NFT）。 NFT是 由成对螺旋丝（PHF）单根直丝组成 (SSF)它们在AD脑切片中的密度与 疾病的严重性。虽然NFT是最明显的异常 在细胞水平上发生在AD中的结构，它们的形成， 持久性和最终的神经毒性最有可能引起更多的 微妙的异常代谢变化，最终由细胞指导 基因组 因此，对这些因素的理解 对于它们的形成，以及在NFT的情况下，它们的 不溶性和蛋白酶抗性可能提供线索， AD的潜在病因。 该提案的核心目标是 调查一些被认为是引发 PHF的形成和维持其结构。 在过去的十年里，许多生物化学和免疫学研究已经 显示PHF由微管相关蛋白tau组成 （PHF-tau）。 正常tau蛋白和PHF之间的主要区别之一- tau的一个重要特征是PHF-tau似乎被ser/thr更高度磷酸化， 亲定向激酶。 由于磷酸化的tau蛋白显示结合减少， 对于微管，PHF组装的合理假设是 tau蛋白的初始磷酸化，这又导致自身结合 蛋白质单体转化成纤维。 本提案的目标之一 是为了确定磷酸化是否真的能诱导构象 与已知的Tau序列同源的肽的变化 微管结合的重要性。 最近，已经发现非磷酸化的全长tau蛋白是 能够在生理条件下形成PHF样细丝， 在存在糖胺聚糖（例如肝素）的情况下体外孵育 和硫酸肝素。此外，当存在以下情况时，可以形成单丝： 一种18个氨基酸的肽，来源于 将tau与肝素或聚-L-谷氨酸一起孵育。 使用 生物物理方法，我们打算研究构象变化，在这一点上， 纤维诱导下产生的多肽和同源多肽 条件 这将解决一个假设， 构象变化是纤维形成的先决条件。 任何构象变化的详细模型将从CD中推导出来。 和NMR/距离几何方法。