CONFORMATION OF PHOSPHORYLATED BRAIN PEPTIDES

阿尔茨海默病（AD）和其他一些神经退行性疾病是 以神经系统缠结的逐渐积累为特征 (NFT)和富含淀粉样蛋白的老年斑（SP）。 虽然不限于AD， SP和NFT的数量与痴呆的严重程度相关。 的 缠结最有可能是由tau形成的，tau是一种微管相关的 蛋白质和其他脑蛋白质，如神经丝（NF）。 我们 鉴定了人tau蛋白上的丝氨酸残基，当磷酸化时， 将正常蛋白质改变为A68，这是一组AD- 在NFT中特异性和存在。 我们还证明了在某些情况下， 人NF和tau蛋白合成肽构象 从螺旋转弯结构到β-折叠片， 在电子显微镜水平上的缠结的特征。 磷酸化可能在功能中也起着至关重要的作用， 运输、降解等，这些和其他神经细胞骨架 proteins. NF和tau的磷酸化位点嵌入在类似的 氨基酸区域，并具有高的金属离子结合潜力。 我们建议合成非磷酸化和磷酸化肽 对应于人tau蛋白的正常和异常磷酸化位点 蛋白 我们将使用圆二色性（CD），核磁共振 (NMR)和傅里叶变换红外（FT-IR）光谱，以确定 肽在不同溶剂和环境中的构象 条件 我们正在寻找磷酸盐受体位点， 异常后分子间聚集体形成的核心 翻译修饰改变了构象。 我们亦建议 将这些研究扩展到那些促使沉积的NF片段， 因此产生了已知的NFT的微观结构。 这些研究将深入了解地形和环境 AD中异常蛋白质沉积的要求。

Alzheimer's disease (AD) and some other neurodegenerative diseases are characterized by a progressive accumulation of neurofibrillary tangles (NFT) and amyloid-rich senile plaques (SP). Although not restricted to AD, the number of SPs and NFTs correlates with the severity of dementia. The tangles are most probably formed from tau, a microtubule-associated protein, and other brain proteins, like neurofilaments (NFs). We identified a serine residue on human tau which, when phosphorylated, changes the normal protein to A68, a group of polypeptides that are AD- specific and present in NFTs. We also demonstrated that in certain circumstances, phosphorylation changes the conformation of synthetic peptides corresponding to human NF and tau from a helical-turn structure to beta-pleated sheets that are characteristic of the tangles at the electron microscopic level. Phosphorylation probably also plays a vital role in the function, transport, degradation, etc., of these and other neuronal cytoskeletal proteins. The phosphorylation sites of NF and tau are embedded in similar amino acid regions and have a high metal ion binding potential. We propose to synthesize non-phosphorylated and phosphorylated peptides corresponding to normal and abnormal phosphorylation sites of human tau protein. We will use circular dichroism (CD), nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopy to determine the conformation of the peptides in different solvents and environmental conditions. We are looking for phosphate acceptor sites that may serve as cores for intermolecular aggregate formation after abnormal post- translational modifications have changed the conformation. We also propose to extend these studies to those fragments of NF that abet the deposition of tau and thereby give rise to the known microscopic structure of NFTs. These studies will give insights into the topographical and environmental requirements for deposits of abnormal proteins in AD.