Structure and membrane binding of alpha-synuclein
α-突触核蛋白的结构和膜结合
基本信息
- 批准号:7967275
- 负责人:
- 金额:$ 28.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAmidesBindingBiological ProcessC-terminalCharacteristicsDataDiseaseEnvironmentExhibitsFluorescence AnisotropyKineticsLipid BindingLipidsMembraneModelingMolecular ConformationParkinson DiseasePeptidesPhospholipidsProcessPropertyProteinsRegulationRoleS-1 Antimetabolite agentSolutionsStructureSurfaceSynapsesSynaptic VesiclesTitrationsVesiclealpha synucleindopaminergic neuroninsightmimeticsmutantstoichiometry
项目摘要
In dopaminergic neurons, a-synuclein (aS) partitions between a disordered cytosolic state and a lipid-bound state. Binding of aS to membrane phospholipids is implicated in its functional role of synaptic regulation, but also impacts fibril formation associated with Parkinsons disease. We describe here a solution NMR study in which aS is added to small unilamellar vesicles of a composition mimicking synaptic vesicles; the results provide evidence for multiple distinct phospholipid-binding modes of aS. Exchange between the free and lipid-bound aS state, and between the different bound states, is slow on the NMR timescale, being in the range of 1-10 s-1. Partitioning of the binding modes is dependent on the lipid:aS stoichiometry, and tight binding with slow exchange kinetics is observed at stoichiometries as low as 2:1. In all lipid-bound states, a segment of residues starting at the N-terminus of aSadopts an a-helical conformation while succeeding residues retain characteristics of a random coil. The C-terminal 40 residues remain dynamically disordered, even at high lipid concentration, but can also bind to lipids to an extent that appears to be determined by the fraction of cis X-Pro peptide bonds in this region. While lipid-bound aS exhibits dynamical properties that preclude its direct observation by NMR, its exchange with the NMR-visible free form allows for its indirect characterization. Rapid amide-amide NOE buildup points to a large a-helical conformation, and a distinct increase in fluorescence anisotropy attributed to Tyr39 indicates an ordered environment for this dark state. Titration of aS with increasing amounts of lipids suggests that the binding mode under high lipid conditions remains qualitatively similar to the low-lipid case. The NMR data appear incompatible with the commonly assumed model where aS lies in an a-helical conformation on the membrane surface, and instead suggest that considerable remodeling of the vesicles is induced by aS.
在多巴胺能神经元中,α-突触核蛋白(aS)在无序的胞质状态和脂质结合状态之间分配。aS与膜磷脂的结合涉及其突触调节的功能作用,但也影响与帕金森病相关的原纤维形成。我们在这里描述了一个解决方案的NMR研究,其中aS被添加到小的单层囊泡的组合物模仿突触囊泡,结果提供了证据,多个不同的磷脂结合模式的aS。 游离态和脂质结合态之间以及不同结合态之间的交换在NMR时间尺度上是缓慢的,在1-10 s-1的范围内。 结合模式的分配取决于脂质:aS的化学计量,并且在低至2:1的化学计量下观察到具有缓慢交换动力学的紧密结合。 在所有的脂质结合状态下,一段残基开始在N-末端的aS采用a-螺旋构象,而随后的残基保留的随机线圈的特性。 C-末端40个残基保持动态无序,即使在高脂质浓度,但也可以结合到脂质的程度似乎是由该区域中的顺式X-Pro肽键的分数确定。虽然脂质结合的aS表现出动力学性质,排除其直接观察NMR,其与NMR可见的自由形式的交换允许其间接表征。 酰胺-酰胺NOE的快速积累指向大的α-螺旋构象,并且归因于Tyr 39的荧光各向异性的明显增加表明这种暗态的有序环境。 随着脂质量的增加滴定的aS表明,在高脂质条件下的结合模式仍然定性类似于低脂质的情况。的NMR数据出现不兼容的通常假设的模型,其中aS位于膜表面上的a-螺旋构象,而不是建议,相当大的重构的囊泡诱导的aS。
项目成果
期刊论文数量(0)
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{{ truncateString('Ad Bax', 18)}}的其他基金
Structural study of the HIV1 gp41 coat protein
HIV1 gp41外壳蛋白的结构研究
- 批准号:
7967823 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
Structural study of the HIV1 gp41 coat protein
HIV1 gp41外壳蛋白的结构研究
- 批准号:
8939688 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
Protein structure and dynamics from residual dipolar couplings
残余偶极耦合的蛋白质结构和动力学
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8148713 - 财政年份:
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$ 28.11万 - 项目类别:
Sructural study of immuno regulatory proteins by NMR spectroscopy
通过核磁共振波谱研究免疫调节蛋白的结构
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9357217 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
Protein structure and dynamics from residual dipolar couplings
残余偶极耦合的蛋白质结构和动力学
- 批准号:
7967277 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
Protein and nucleic acid structure and dynamics from residual dipolar couplings
残余偶极耦合的蛋白质和核酸结构和动力学
- 批准号:
8349704 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
Structural study of the HIV1 gp41 coat protein
HIV1 gp41外壳蛋白的结构研究
- 批准号:
8553623 - 财政年份:
- 资助金额:
$ 28.11万 - 项目类别:
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