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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 α-突触核蛋白(AS)是一种高度保守的突触前蛋白，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。然而，AS淀粉样蛋白纤维的积聚被认为是帕金森病发生的主要原因。α-突触核蛋白的三个单点突变，即A30P、A53T和E46K(以及AS基因的三倍体)被认为与一种罕见的家族性帕金森病(PD)有关。另一方面，绝大多数与路易身体相关的疾病病例是散发性的，涉及野生型AS。S的正常功能涉及蛋白质与膜的相互作用，在这种作用下，蛋白质从胞浆中的无序结构转变为膜结合状态下的高度螺旋结构。脉冲偶极ESR已经成功地用于表征结合在十二烷基硫酸钠胶束和磷脂膜上的野生型结构[1，2]。 我们对Pd连接突变体A30P、E46K和A53T在膜结合状态下的结构性质进行了详细的研究，旨在阐明野生型AS及其Pd连接衍生物之间的最终差异。后者可能对了解帕金森病的发病机制有重要意义。我们还研究了溶液中所有游离态的ASS的结构。