α-Synuclein (αS) plays a key role in Parkinson's disease (PD). The αS nuclear role, its binding affinity and specificity to histones and dsDNA remains unknown. Here, we have measured the binding affinity ($K_d$) between αS wild-type (wt) and PD-specific αS S129-phosphorylation mimicking (S129E) mutant with full-length and flexible tail truncated individual core histones (H2a, H2b, H3, and H4), linker histone (H1), and carried out αS-dsDNA interaction studies. This study revealed that αS(wt) interacts specifically with N-terminal flexible tails of histone H3, H4, and flexible tails of H1. The αS(S129E) mutant recognizes histones similar to αS(wt) but binds with higher affinity. Intriguingly, αS(S129E) showed a binding affinity for control proteins (bovine serum albumin and lysozyme), while no interaction was seen for αS(wt). Based on our above observation, we contemplate that the physio-chemical properties of αS with S129-phosphorylation has changed compared to αS(wt), resulting in interaction for other proteins, which is the basis for Lewy body formation. Besides, this study showed αS binding to dsDNA is weak and nonspecific. Overall, αS specificity for histone binding suggests that its nuclear role is possibly driven through histone interaction.

中文翻译：

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α-突触核蛋白与单个人类核心组蛋白、接头组蛋白和 dsDNA 相互作用的分子见解

α-突触核蛋白 (αS) 在帕金森病 (PD) 中起关键作用。αS 核作用、其对组蛋白和 dsDNA 的结合亲和力和特异性仍然未知。在这里，我们测量了结合亲和力（${ķ}_d$) 在 αS 野生型 (wt) 和 PD 特异性 αS S129-磷酸化模拟 (S129E) 突变体之间，具有全长和柔性尾部截断的单个核心组蛋白 (H2a、H2b、H3 和 H4)、接头组蛋白 (H1)、并进行了αS-dsDNA相互作用研究。这项研究表明，αS(wt) 与组蛋白 H3、H4 的 N 末端柔性尾和 H1 的柔性尾特异性相互作用。αS(S129E) 突变体识别与αS(wt) 相似的组蛋白，但以更高的亲和力结合。有趣的是，αS(S129E) 对对照蛋白（牛血清白蛋白和溶菌酶）显示出结合亲和力，而对 αS(wt) 没有观察到相互作用。基于我们上述观察，我们认为具有 S129 磷酸化的 αS 的理化性质与 αS(wt) 相比发生了变化，导致与其他蛋白质的相互作用，这是路易体形成的基础。此外，这项研究表明，αS 与 dsDNA 的结合较弱且非特异性。总体而言，组蛋白结合的 αS 特异性表明其核作用可能是通过组蛋白相互作用驱动的。