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 以逐渐积累的神经原纤维缠结为特征的 (NFT)和富含淀粉样蛋白的老年斑(SP)。虽然并不局限于公元前， SP和NFT的数量与痴呆症的严重程度相关。这个 缠结很可能是由tau形成的，tau是一种与微管相关的物质。 蛋白质，以及其他大脑蛋白质，如神经细丝(NFs)。我们 在人类tau上发现了一种丝氨酸残基，当它被磷酸化时， 将正常蛋白质改变为A68，这是一组属于AD的多肽- 具体存在于NFT中。 我们还证明，在某些情况下，磷酸化会改变 人神经营养因子和tau蛋白合成肽的构象 从螺旋转向结构到贝塔褶皱的薄片 在电子显微镜水平上的缠结特征。 磷酸化可能也在功能中起着至关重要的作用， 这些和其他神经细胞骨架的运输、降解等 蛋白质。NF和tau的磷酸化位点嵌入在类似的 氨基酸区域，并具有很高的金属离子结合潜力。 我们建议合成非磷酸化和磷酸化的多肽 与人tau蛋白的正常和异常磷酸化位点相对应 蛋白。我们将使用圆二色谱(CD)、核磁共振 核磁共振和傅里叶变换红外光谱分析 多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置，可以作为 异常后处理后分子间聚集体形成的核心 翻译修饰改变了构象。我们还提议 将这些研究扩展到那些助长沉积的核因子片段 从而产生了已知的NFTs的微观结构。 这些研究将使人们对地形和环境有更深入的了解 阿尔茨海默病对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.