Department of Chemistry, Imperial College London, White City Campus, London, W12 0BZ, UK.
Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
Chemphyschem. 2021 Dec 3;22(23):2413-2419. doi: 10.1002/cphc.202100651. Epub 2021 Oct 14.
The interaction between α-synuclein (αSyn) and Cu has been suggested to be closely linked to brain copper homeostasis. Disruption of copper levels could induce misfolding and aggregation of αSyn, and thus contribute to the progression of Parkinson's disease (PD). Understanding the molecular mechanism of αSyn-Cu interaction is important and controversies in Cu coordination geometry with αSyn still exists. Herein, we find that the pathological H50Q mutation has no impact on the kinetics of Cu binding to the high-affinity site of wild type αSyn (WT-αSyn), indicating the non-involvement of His50 in high-affinity Cu binding to WT-αSyn. In contrast, the physiological N-terminally acetylated αSyn (NAc-αSyn) displays several orders of magnitude weaker Cu binding affinity than WT-αSyn. Cu coordination mode to NAc-αSyn has also been proposed based on EPR spectrum. In addition, we find that Cu coordinated WT-αSyn is reduction-active in the presence of GSH, but essentially inactive towards ascorbate. Our work provides new insights into αSyn-Cu interaction, which may help understand the multifaceted normal functions of αSyn as well as pathological consequences of αSyn aggregation.
α-突触核蛋白（αSyn）与铜的相互作用与大脑铜稳态密切相关。铜水平的破坏可能导致αSyn 的错误折叠和聚集，从而导致帕金森病（PD）的进展。了解αSyn-Cu 相互作用的分子机制很重要，并且αSyn 与 Cu 的配位几何结构仍存在争议。在此，我们发现病理性 H50Q 突变对 Cu 与野生型αSyn（WT-αSyn）高亲和力结合位点的结合动力学没有影响，这表明 His50 不参与 WT-αSyn 与高亲和力 Cu 的结合。相比之下，生理上 N 端乙酰化的αSyn（NAc-αSyn）与 WT-αSyn 相比，Cu 结合亲和力弱几个数量级。还根据 EPR 光谱提出了 NAc-αSyn 的 Cu 配位模式。此外，我们发现 GSH 存在时，Cu 配位的 WT-αSyn 具有还原活性，但对抗坏血酸基本没有活性。我们的工作为 αSyn-Cu 相互作用提供了新的见解，这可能有助于理解 αSyn 的多方面正常功能以及 αSyn 聚集的病理后果。
