Bloch Daniel N, Kolkowska Paulina, Tessari Isabella, Baratto Maria Camilla, Sinicropi Adalgisa, Bubacco Luigi, Mangani Stefano, Pozzi Cecilia, Valensin Daniela, Miller Yifat
Department of Chemistry , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel.
The Ilse Katz Institute for Nanoscale Science & Technology , Ben-Gurion University of the Negev , Be'er Sheva 84105 , Israel.
Inorg Chem. 2019 Aug 19;58(16):10920-10927. doi: 10.1021/acs.inorgchem.9b01337. Epub 2019 Aug 1.
The effect of Cu on α-synuclein (AS) aggregation is important because clinical studies of patients with Parkinson's disease have shown elevated levels of Cu in the cerebrospinal fluid. So far, the molecular architectures of Cu-AS fibril complexes at atomic resolution are unknown. The current work identifies for the first time that His50 cannot bind Cu ions in mature fibrils. Moreover, it shows hopping of Cu ions between residues in AS fibrils and changes in the Cu coordination mode in Cu ions that bind in the termini of AS. The current study combines extensive experimental techniques, density functional theory calculations, and computational modeling tools to provide a complete description of the Cu binding site in AS fibrils. Our findings illustrate for the first time the specific interactions between Cu ions and AS fibrils, suggesting a new mechanistic perspective on the effect of Cu ions on AS aggregation.
铜对α-突触核蛋白（AS）聚集的影响至关重要，因为帕金森病患者的临床研究表明脑脊液中的铜水平升高。到目前为止，原子分辨率下铜-AS纤维复合物的分子结构尚不清楚。目前的工作首次确定His50在成熟纤维中不能结合铜离子。此外，它还显示了铜离子在AS纤维中的残基之间跳跃，以及结合在AS末端的铜离子的配位模式变化。当前的研究结合了广泛的实验技术、密度泛函理论计算和计算建模工具，以完整描述AS纤维中的铜结合位点。我们的研究结果首次阐明了铜离子与AS纤维之间的特定相互作用，为铜离子对AS聚集的影响提出了新的机制观点。
