Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China.
Molecules. 2022 Dec 1;27(23):8383. doi: 10.3390/molecules27238383.
Amyloid fibrillation of α-synuclein is implicated in the pathogenesis of Parkinson's disease and heavy metal ions such as Fe, Zn, and Cu are known to be involved in the process. In this work, we explored the use of FTIR spectroscopy to look into the modulation effects of Fe, Zn, and Cu on the amyloid fibrillation of α-synuclein. We performed a curve-fitting analysis on the FTIR amide I bands of these α-synuclein fibril systems, namely, the pristine fibril and the fibrils prepared in the presence of Fe, Zn, and Cu. We found that the α-synuclein fibrils under the influences of metal ions all possessed a parallel β-sheet structure, turn structure, and disordered structure, similar to that of pristine α-synuclein fibril. We also observed metal-induced increases in the proportions of the β-sheet secondary structure within the α-synuclein fibrils, with Fe being the most effective inducer. We performed second derivative analysis of the side chain carboxylic groups of α-synuclein fibrils and found that the side chain microenvironment of the α-synuclein fibrils was more influenced by Fe than Zn, and Cu. In addition, our atomic force microscopic study revealed that the morphologies of α-synuclein fibrils under the influence of Fe was quite different from that of the Zn and Cu systems. Our FTIR results suggested that the modulation effects of Fe, Zn, and Cu on α-synuclein fibrillation occurred at both secondary and quaternary structural levels. At last, we proposed a mechanistic hypothesis to interpret how metal ions could affect the morphology of α-synuclein amyloid fibril based on the conformational plasticity properties of intrinsically disordered proteins.
α-突触核蛋白的淀粉样纤维形成与帕金森病的发病机制有关，已知重金属离子如铁、锌和铜参与了这一过程。在这项工作中，我们探索了使用傅里叶变换红外（FTIR）光谱研究铁、锌和铜对α-突触核蛋白淀粉样纤维形成的调制作用。我们对这些α-突触核蛋白原纤维系统的 FTIR 酰胺 I 带进行了曲线拟合分析，即原始纤维和在存在铁、锌和铜的情况下制备的纤维。我们发现，在金属离子影响下的α-突触核蛋白纤维都具有平行的β-折叠结构、转角结构和无序结构，类似于原始的α-突触核蛋白纤维。我们还观察到金属诱导的α-突触核蛋白纤维中β-折叠二级结构比例增加，其中铁的诱导效果最强。我们对α-突触核蛋白纤维的侧链羧酸基团进行了二阶导数分析，发现铁对α-突触核蛋白纤维的侧链微环境的影响大于锌和铜。此外，我们的原子力显微镜研究表明，铁影响下的α-突触核蛋白纤维的形态与锌和铜系统的形态有很大的不同。我们的 FTIR 结果表明，铁、锌和铜对α-突触核蛋白纤维形成的调制作用发生在二级和四级结构水平上。最后，我们根据无规卷曲蛋白质的构象可塑性特性提出了一个机制假设，解释了金属离子如何影响α-突触核蛋白淀粉样纤维的形态。
