Peculiarities of Copper Binding to α-Synuclein
Peculiarities of Copper Binding to α-Synuclein
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DOI：
10.1080/073911012010525023
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Uversky, Vladimir N.
中科院分区：
文献类型：
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作者：
Ahmad, Atta;Burns, Colin S.;Uversky, Vladimir N.
重金属已被认为是最普遍的神经退行性疾病发病机制的病原体。已经提出了各种机制来解释金属的毒性作用，从金属诱导的蛋白质氧化到金属诱导的蛋白质构象改变。α -突触核蛋白的聚集与帕金森病（PD）有关，包括铜在内的各种金属构成了a-突触核蛋白聚集增强剂的重要群体。在这项研究中，我们系统地表征了α -synuclein- cu2 +结合位点，并使用一组生物物理技术，如电子顺磁共振（EPR）、电子自旋回波包络调制（ESEEM）、圆二色性（CD）和尺寸排除色谱（SEC），分析了金属结合在a-synuclein纤维性颤动中的可能作用。我们的分析表明，a-synuclein具有至少两个Cu2+的结合位点。我们已经能够在n端区域定位一个结合位点。此外，基于模型肽和β -突触核蛋白的EPR研究，我们得出结论，可疑的His残基似乎没有参与强Cu2+结合。
Heavy metals have been implicated as the causative agents for the pathogenesis of the most prevalent neurodegenerative disease. Various mechanisms have been proposed to explain the toxic effects of metals ranging from metal-induced oxidation of protein to metal-induced changes in the protein conformation. Aggregation of alpha-synuclein is implicated in Parkinson's disease (PD), and various metals, including copper, constitute a prominent group of a-synuclein aggregation enhancers. In this study, we have systematically characterized the alpha-synuclein-Cu2+ binding sites and analyzed the possible role of metal binding in a-synuclein fibrillation using a set of biophysical techniques, such as electron paramagnetic resonance (EPR), electron spin-echo envelope modulation (ESEEM), circular dichroism (CD), and size exclusion chromatography (SEC). Our analyses indicated that a-synuclein possesses at least two binding sites for Cu2+. We have been able to locate one of the binding sites in the N-terminal region. Furthermore, based on the EPR studies of model peptides and beta-synuclein, we concluded that the suspected His residue did not appear to participate in strong Cu2+ binding.