α-synuclein has a high affinity for packing defects in a bilayer membrane -: A thermodynamics study
α-synuclein has a high affinity for packing defects in a bilayer membrane -: A thermodynamics study
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DOI：
10.1074/jbc.m401076200
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发表时间：
2004-05-21
影响因子：
4.8
通讯作者：
Beyer, K
中科院分区：
文献类型：
--
作者：
Nuscher, B;Kamp, F;Beyer, K
许多神经退行性疾病，包括帕金森病、路易体痴呆和多系统萎缩，其特征在于含有高比例的α-突触核蛋白（α S）的纤维状聚集体的细胞内沉积。与膜-水界面的相互作用强烈地调节蛋白质的折叠和聚集。本研究采用滴定量热法、差示扫描量热法和圆二色谱法研究了α S的脂质结合和螺旋-螺旋转变。滴定的蛋白质与小的单层囊泡组成的两性离子磷脂以下的链熔化温度的脂质产生异常大的放热热值。在一个简单的模型，假设在囊泡表面的饱和结合位点的S形滴定曲线进行了评价。由于同时结合和螺旋折叠，累积热释放和椭圆度呈线性相关。在大的单层囊泡存在下，α S没有热释放和折叠，这表明小的曲率半径对于α S-膜相互作用是必要的。蛋白质-囊泡相互作用的热释放和负热容不能单独归因于蛋白质的卷曲-螺旋转变。我们推测，结合和螺旋折叠的α S依赖于存在的缺陷结构中的膜-水界面，这反过来又导致在高度弯曲的囊泡膜中的脂质排序。这将讨论关于一个可能的作用的蛋白质的突触囊泡膜的稳定。
A number of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are characterized by the intracellular deposition of fibrillar aggregates that contain a high proportion of alpha-synuclein (alphaS). The interaction with the membrane-water interface strongly modulates folding and aggregation of the protein. The present study investigates the lipid binding and the coil-helix transition of alphaS, using titration calorimetry, differential scanning calorimetry, and circular dichroism spectroscopy. Titration of the protein with small unilamellar vesicles composed of zwitterionic phospholipids below the chain melting temperature of the lipids yielded exceptionally large exothermic heat values. The sigmoidal titration curves were evaluated in terms of a simple model that assumes saturable binding sites at the vesicle surface. The cumulative heat release and the ellipticity were linearly correlated as a result of simultaneous binding and helix folding. There was no heat release and folding of alphaS in the presence of large unilamellar vesicles, indicating that a small radius of curvature is necessary for the alphaS-membrane interaction. The heat release and the negative heat capacity of the protein-vesicle interaction could not be attributed to the coil-helix transition of the protein alone. We speculate that binding and helix folding of alphaS depends on the presence of defect structures in the membrane-water interface, which in turn results in lipid ordering in the highly curved vesicular membranes. This will be discussed with regard to a possible role of the protein for the stabilization of synaptic vesicle membranes.