PROBING ALPHA-SYNUCLEIN AGGREGATION
探测 α-突触核蛋白聚集
基本信息
- 批准号:8364109
- 负责人:
- 金额:$ 0.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Amyloid FibrilsBehaviorBindingCysteineCytosolDevelopmentDiseaseDopamineEnvironmentFundingGoalsGrantHomeostasisLearningLewy BodiesLinkMaintenanceMembraneMembrane ProteinsMicellesMolecular ConformationNational Center for Research ResourcesParkinson DiseasePhospholipidsPhysiologic pulsePoint MutationPrincipal InvestigatorPropertyProteinsRegulationResearchResearch InfrastructureResourcesSourceSpin LabelsStructureSynapsesTechnologyUnited States National Institutes of HealthVariantalpha synucleinalpha synuclein genecostmimeticsmutantpresynapticprotein aggregation
项目摘要
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 hallmark 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 a disordered structure in cytosol to the highly helical one in membrane-bound state. In several completed subprojects we have successfully applied Pulsed dipolar ESR to characterize the behavior of wild type aS bound to SDS micelles and phospholipid membranes [1, 2].
In our detailed study on the structural properties of WT and PD-linked mutants A30P, E46K and A53, we showed that all variants of aS posses the propensity to switch between broken and extended helix conformations, depending on aS environment [1-3]. Yet, there is insufficient information about the factors that trigger and govern the aggregation of this protein. Therefore, we undertook a study that has as its goal to learn whether and how the interaction with the common membrane mimetics, such as SDS, could initiate the aggregation of aS. So far, we have studied the interaction with SDS of single spin-labeled cysteine mutants of aS. [1] Borbat, P.; Ramlall, T. F.; Freed, J. H.; Eliezer, D. J. Am. Chem. Soc., 2006, 128, 10004-10005. [2] Elka R. Georgieva, Trudy F. Ramlall, Peter P. Borbat, Jack H. Freed, David Eliezer, J. Am. Chem. Soc. 2008, 130, 12856-12857. [3] E.R. Georgieva, T.F. Ramlall, P.P. Borbat, J.H. Freed, D. Eliezer, J Biol Chem, 285 (2010) 28261-28274.
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淀粉样纤维的积累被认为是帕金森病发展的标志。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。在几个已完成的子项目中,我们已经成功地应用脉冲偶极ESR来表征结合在十二烷基硫酸钠胶束和磷脂膜上的野生型的行为[1,2]。
在我们对WT和Pd连锁突变体A30P、E46K和A53的结构性质的详细研究中,我们发现AS的所有变体都有在断裂和延伸的螺旋构象之间切换的倾向,这取决于AS的环境[1-3]。然而,关于触发和控制这种蛋白质聚集的因素的信息不足。因此,我们开展了一项研究,目的是了解与常见的膜模拟物如十二烷基硫酸钠的相互作用是否以及如何启动AS的聚集。到目前为止,我们已经研究了AS的单自旋标记半胱氨酸突变体与SDS的相互作用。[1]Borbat,P.;Ramlall,T.F.;Freed,J.H.;Eliezer,D.J.Am化学。社会科学院,2006年,第128,10004-10005。[2]Elka R.Georgieva,Trudy F.Ramlall,Peter P.Borbat,Jack H.Freed,David Eliezer,J.Am化学。SoC。2008年,130年,12856-12857。[3]E.R.Georgieva,T.F.Ramlall,P.P.Borbat,J.H.Freed,D.Eliezer,J Biol Chem,第285(2010)28261-28274页。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ELKA R GEORGIEVA其他文献
ELKA R GEORGIEVA的其他文献
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{{ truncateString('ELKA R GEORGIEVA', 18)}}的其他基金
USE OF LIPIDIC NANODISCS FOR STRUCTURE/FUNCTION STUDIES ON MEMBRANE PROTEINS
使用脂质纳米圆盘进行膜蛋白的结构/功能研究
- 批准号:
8364070 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
FREEZE-QUENCH STUDY ON PROTEIN CONFORMATION STATE
蛋白质构象状态的冷冻淬灭研究
- 批准号:
8364073 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
PROBING BACTERIAL HOMOLOGUE OF GLUTAMATE TRANSPORTER BY PULSED DIPOLAR ESR
通过脉冲偶极 ESR 探测谷氨酸转运蛋白的细菌同源物
- 批准号:
8364071 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
BUILDING UP THE FACILITY FOR MEMBRANE PROTEIN MANIPULATION AND SPIN LABELING
建立膜蛋白操作和旋转标记设施
- 批准号:
8364069 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
PULSED DIPOLAR ESR STUDY ON MEMBRANE-BOUND ALPHA-SYNUCLEIN
膜结合 α-突触核蛋白的脉冲偶极 ESR 研究
- 批准号:
8364019 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
INCREASING THE DISTANCE RANGE AND RESOLUTION IN PULSED DIPOLAR ESR SPECTROSCOPY
提高脉冲偶极 ESR 光谱的距离范围和分辨率
- 批准号:
8364033 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
PULSED DIPOLAR ESR STUDY ON MEMBRANE OF EBOLA VIRUS FUSION PEPTIDE
埃博拉病毒融合肽膜的脉冲偶极ESR研究
- 批准号:
8364030 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
STRUCTURE DETERMINATION OF EBOLA VIRUS VP35 PROTEIN BY PDS
PDS 测定埃博拉病毒 VP35 蛋白的结构
- 批准号:
8364072 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
PDS STUDY ON HUMAN PGP MDR TRANSPORTER ABCB1
人类 PGP MDR 转运蛋白 ABCB1 的 PDS 研究
- 批准号:
8364053 - 财政年份:2011
- 资助金额:
$ 0.99万 - 项目类别:
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