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: 8172193
• 负责人: ELKA R GEORGIEVA
• 金额: $ 1.15万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172193
• 关键词: Amyloid Fibrils; Asses; Binding; Computer Retrieval of Information on Scientific Projects Database; Cytosol; Development; Disease; Dopamine; Funding; Grant; Hand; Homeostasis; Institution; Lewy Bodies; Link; Maintenance; Membrane; Membrane Proteins; Micelles; Parkinson Disease; Physiologic pulse; Point Mutation; Property; Proteins; Regulation; Research; Research Personnel; Resources; Solutions; Source; Structure; Synapses; United States National Institutes of Health; alpha synuclein; alpha synuclein gene; insight; mutant; presynaptic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 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，它还参与多个控制点的细胞内多巴胺水平的调节，但 aS 淀粉样原纤维的积累被认为是主要的。帕金森病发生的原因是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）与一种罕见的家族性帕金森病 (PD) 有关，另一方面，绝大多数路易体相关疾病病例是散发性的，且涉及野生型帕金森病。 aS 的正常功能。脉冲偶极 ESR 已成功应用于表征与 SDS 胶束和磷脂膜结合的野生型 aS 的结构 [1, 2]。 我们对膜结合状态下的 PD 连锁突变体 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 连锁衍生物之间的最终差异，后者可能对理解 aS 具有重要意义。我们还研究了溶液中所有自由状态的AS的结构。