Copper binding to the physiological form of the alpha-synuclein protein

铜与 α-突触核蛋白的生理形式结合

• 批准号: 240921625
• 负责人: Professor Dr. Paolo Carloni
• 金额: --
• 依托单位: Bereich Computational Biomedicine (IAS-5/INM-9)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/240921625?language=en
• 关键词: Copper; binding; physiological; form; alpha

The human alpha-synuclein (AS) protein is associated with the pathogenesis of Parkinsons disease (PD) and other neurodegenerative disorders. In PD, AS is the primary component of Lewy-bodies, a proteinaceous deposit in the substantia nigra (a part of the midbrain). The causes and mechanisms of the self-aggregation of AS protein are unknown. Copper ions, which are found to be harmful in Alzheimers disease, accelerate aggregation of the non-physiological, non-acetylated form of AS in aqueous solution, where the protein is naturally unfolded. Both Cu(I) and Cu(II) ions may play a role in the neuron derangement associated with PD. While structural insights on the non-acetylated, non-physiological form are available, those on the physiologically relevant acetylated form (AcAS) are lacking. However, spectral properties of the Cu(I)-AS form are very similar to the ones of Cu(I)-AcAS. Thus, the conclusions of structural studies regarding Cu(I)-AS remain basically valid for Cu(I)-AcAS. This contrasts with Cu(II) binding to AcAS, which is completely different from that to AS. Here we plan to predict Cu(II)-AcAS structural determinants by molecular simulation. Comparison between calculated NMR, EXAFS and CD spectra and the experimental ones, measured by our collaborator Claudio Fernandez for this research, will establish the reliability of our predictions. Our study may provide the first valuable new insights on how metals, in particular copper, modulate AS fibril formation process. This could be crucial for the development of new drug-design approaches.

人α-突触核蛋白（AS）蛋白与帕金森氏病（PD）和其他神经退行性疾病的发病机理有关。在PD中，就像Lewy-Bodies的主要成分一样，Nigra（中脑的一部分）中的蛋白质沉积物。 AS蛋白自我聚集的原因和机制尚不清楚。铜离子在阿尔茨海默氏病中被发现有害，加速了非生理，非乙酰化形式的As在水溶液中的非乙酰化形式，在蛋白质自然地展开。 Cu（i）和Cu（II）离子均可在与PD相关的神经元紊乱中发挥作用。尽管可以使用非乙酰化，非生理形式的结构见解，但缺乏生理相关的乙酰化形式（ACA）的结构见解。但是，cu（i）的光谱特性与cu（i）-ACA的形式非常相似。因此，关于Cu（i）的结构研究的结论基本上对Cu（i）-ACAS仍有效。这与Cu（II）与ACA的结合形成对比，这与ACA完全不同。在这里，我们计划通过分子模拟预测Cu（II）-ACAS结构决定因素。由我们的合作者Claudio Fernandez衡量了计算的NMR，EXAFS和CD光谱与实验性的比较，将确定我们的预测的可靠性。我们的研究可能会提供第一个有价值的新见解，尤其是铜的金属如何调节纤维形成过程。这对于开发新药物设计方法至关重要。