NEW INSIGHTS INTO THE STRUCTURAL PROPERTIES OF ALPHA-SYNUCLEIN AND ITS MUTANTS

对 α-突触核蛋白及其突变体结构特性的新见解

• 批准号: 8364031
• 负责人: ELKA R GEORGIEVA
• 金额: $ 0.26万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364031
• 关键词: Amyloid Fibrils; Asses; Binding; Cytosol; Development; Disease; Dopamine; Funding; Grant; Homeostasis; Lewy Bodies; Link; Maintenance; Membrane; Membrane Proteins; Micelles; National Center for Research Resources; Parkinson Disease; Physiologic pulse; Point Mutation; Principal Investigator; Property; Proteins; Regulation; Research; Research Infrastructure; Resources; Solutions; Source; Structure; Synapses; Technology; United States National Institutes of Health; alpha synuclein; alpha synuclein gene; cost; insight; mutant; presynaptic

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. Alpha-synuclein (aS) is a highly conserved presynaptic protein that participates in synaptic strength maintenance and dopamine homeostasis. It is also involved in regulation of intracellular dopamine levels at several points of control. However, accumulation of aS amyloid fibrils was implicated as the major reason in the development of Parkinson's disease. The three single-point mutations in a-synuclein, namely, A30P, A53T, and E46K, (as well as a triplication of the aS gene) have been linked to a rare familial form of Parkinson's disease (PD). On the other hand the vast majority of Lewy body-related disease cases is sporadic and involves the wild type of aS. Normal functions of ¿S involve protein-membrane interactions upon which the protein undergoes transformations from disordered structure in cytosol to highly helical one in membrane-bound state. Pulsed dipolar ESR was already successfully applied to characterize the structure of wild type aS bound to SDS micelles and phispholipid membranes [1, 2]. We have undertaken a detailed study on the structural properties of PD-linked mutants A30P, E46K and A53T in membrane-bound state, aiming to elucidate eventual differences among wild type aS and its PD-linked derivates. The later might be important to understand the mechanism of PD. We also studied the structure of all aSs in free state in solution.

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。 α-突触核蛋白（AS）是一种高度组成的突触前蛋白，参与突触强度维持和多巴胺稳态。它还参与了几个控制点的细胞内多巴胺水平的调节。但是，淀粉样蛋白原纤维的积累是帕金森氏病发展的主要原因。 A-突触核蛋白的三个单点突变，即A30p，A53T和E46K（以及AS基因的一式序列）与罕见的帕金森氏病（PD）有关。另一方面，绝大多数与Lewy身体相关的疾病病例都是零星的，涉及AS的野生类型。 S的正常功能涉及蛋白质 - 膜相互作用，蛋白质从细胞质中的无序结构转变为在膜结合状态下的高度螺旋形的转化。脉冲偶极ESR已经成功地用于表征野生型的结构与SDS胶束和腓脂膜结合[1，2]。 我们已经在膜结合的状态下对PD连接突变体A30P，E46K和A53T的结构特性进行了详细研究，旨在阐明野生型AS及其PD链接导数之间的最终差异。后来了解PD的机制可能很重要。我们还研究了解决方案中自由状态下所有屁股的结构。