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.

人类α-突触核蛋白(AS)与帕金森氏病(PD)和其他神经退行性疾病的发病机制有关。在帕金森病中，AS是路易小体的主要成分，路易小体是黑质(中脑的一部分)中的一种蛋白质沉积。AS蛋白自聚集的原因和机制尚不清楚。铜离子被发现对阿尔茨海默氏症有害，它会加速非生理性、非乙酰化形式的砷在水溶液中聚集，蛋白质在水溶液中自然展开。铜(I)和铜(II)离子可能在帕金森病相关的神经元排列紊乱中发挥作用。虽然关于非乙酰化、非生理性形式的结构方面的见解是可用的，但关于生理相关的乙酰化形式(ACAs)的结构见解是缺乏的。然而，铜(I)-As的光谱性质与铜(I)-ACAs的光谱性质非常相似。因此，有关铜(I)-As的结构研究结论对于铜(I)-ACAs基本仍然有效。这与铜(II)与AcAs的结合完全不同，与与As的结合完全不同。在这里，我们计划通过分子模拟来预测铜(II)-AcAs的结构决定因素。将计算的核磁共振、EXAFS和CD光谱与我们的合作者克劳迪奥·费尔南德斯为这项研究测量的实验光谱进行比较，将建立我们预测的可靠性。我们的研究可能会为金属，特别是铜，如何作为纤维形成过程的调节提供第一个有价值的新见解。这可能对开发新的药物设计方法至关重要。