Department of Chemistry and Chemical Biology, Rutgers University , Piscataway, New Jersey 08854, United States.
Biochemistry. 2014 May 6;53(17):2815-7. doi: 10.1021/bi5003025. Epub 2014 Apr 22.
α-Synuclein (αS) is an amyloidogenic intrinsically disordered protein implicated in Parkinson's disease, for which copper-mediated pathways of neurodegeneration have been suggested. We have employed nuclear magnetic resonance, circular dichroism, electrospray ionization mass spectrometry, and thioflavin T fluorescence to characterize interactions of Cu(2+) with the physiological acetylated form (Ac-αS). Significantly, N-terminal acetylation abolishes Cu(2+) binding at the high-affinity M1-D2 site present in the nonacetylated protein and maintains Cu(2+) interactions around H50/D121. Fibrillation enhancement observed at an equimolar Cu(2+) stoichiometry with the nonacetylated model does not occur with Ac-αS. These findings open new avenues of investigation into Cu(2+)-mediated neurodegenerative pathology suggested in vivo.
α-突触核蛋白（αS）是一种淀粉样蛋白，与帕金森病有关，有研究表明其涉及铜介导的神经退行性变途径。我们采用核磁共振、圆二色性、电喷雾电离质谱和硫黄素 T 荧光法来表征铜（Ⅱ）与生理乙酰化形式（Ac-αS）的相互作用。值得注意的是，N 端乙酰化作用会使非乙酰化蛋白中存在的高亲和力 M1-D2 位点上的铜（Ⅱ）结合被取消，同时维持 H50/D121 附近的铜（Ⅱ）相互作用。与非乙酰化模型在等摩尔铜（Ⅱ）化学计量比下观察到的纤维增强作用在 Ac-αS 中不会发生。这些发现为体内提出的铜（Ⅱ）介导的神经退行性病理提供了新的研究途径。
