Common structural features of toxic intermediates from α-synuclein and GroES fibrillogenesis detected using cryogenic coherent X-ray diffraction imaging
Common structural features of toxic intermediates from α-synuclein and GroES fibrillogenesis detected using cryogenic coherent X-ray diffraction imaging
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DOI：
10.1093/jb/mvw052
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发表时间：
2017-01-01
影响因子：
2.7
通讯作者：
Kawata, Yasushi
中科院分区：
文献类型：
--
作者：
Kameda, Hiroshi;Usugi, Sayaka;Kawata, Yasushi
突触核蛋白（α Syn）在神经细胞中的聚集和沉积与帕金森病的发病机制有关。尽管α - Syn聚集和原纤维形成的机制已被广泛研究，但直接导致细胞毒性的结构标志仍在争论中。在这里，我们用相干x射线衍射分析比较了α Syn的有毒中间分子种和另一种蛋白质GroES的类似有毒分子种的结构特征。利用SACLA的相干x射线自由电子激光脉冲，分析了α Syn和GroES纤维中间种，并表征了不同的聚集体结构。与先前的研究不同，在先前的研究中，α - Syn的环状低聚形式被识别出来，散射痕迹的颗粒重建表明，有毒颗粒的特定形式是不同的，颗粒的大小落在一个特定的范围内。然而，我们确实在alpha Syn和GroES样本中发现了一个共同的结构特征；在衍射实验中，检测到的粒子边缘几乎平行，并产生了特征衍射图样。在α Syn和GroES纤维形成的有毒中间体中存在平行边缘颗粒，这表明可能存在导致成熟原纤维形成的共同分子界面。
The aggregation and deposition of alpha-synuclein (alpha Syn) in neuronal cells is correlated to pathogenesis of Parkinson's disease. Although the mechanism of alpha Syn aggregation and fibril formation has been studied extensively, the structural hallmarks that are directly responsible for toxicity toward cells are still under debate. Here, we have compared the structural characteristics of the toxic intermediate molecular species of alpha Syn and similar toxic species of another protein, GroES, using coherent X-ray diffraction analysis. Using coherent X-ray free electron laser pulses of SACLA, we analysed alpha Syn and GroES fibril intermediate species and characterized various aggregate structures. Unlike previous studies where an annular oligomeric form of alpha Syn was identified, particle reconstruction from scattering traces suggested that the specific forms of the toxic particles were varied, with the sizes of the particles falling within a specific range. We did however discover a common structural feature in both alpha Syn and GroES samples; the edges of the detected particles were nearly parallel and produced a characteristic diffraction pattern in the diffraction experiments. The presence of parallel-edged particles in toxic intermediates of alpha Syn and GroES fibrillogenesis pointed towards a plausible common molecular interface that leads to the formation of mature fibrils.