The aggregation of tau, a microtubule-associated protein, is known to play an important role in several neurological disorders including Alzheimer's disease. Alzheimer's disease is considered to be associated with the dyshomeostasis of metal ions such as aluminum, zinc, copper, and ferric ions. Tau is predominately acetylated at the K274 residue in Alzheimer's disease, and the acetylation of the K274 residue is thought to be linked with dementia. Using acetyl mimicking K274Q mutation in tau, we have examined the effects of the acetylation at K274 residue of tau on the interactions of tau with metal ions and also on the ability of tau to protect DNA from the heat and other stressors. We found that Zn2+ and Al3+ increased the liquid-liquid phase separation of tau, an initial stage of tau aggregation. Further, Zn2+ and Al3+ considerably reduced the critical concentration for the phase separation of K274Q tau. Using far-UV circular dichroism and fluorescence spectroscopy, we provide evidence suggesting that the binding of Zn2+ and Al3+ induces conformational changes in tau. The K274Q mutation enhanced the binding affinity of tau for Zn2+, Al3+, Cu2+, and Fe3+ ions. In addition, Zn2+, Al3+, Cu2+, and Fe3+ significantly enhanced the aggregation propensity of K274Q tau in comparison to tau. Interestingly, tau binds to DNA with a higher affinity than K274Q tau. Tau protects DNA from the DNase treatment in vitro as well as from the heat stress in neuroblastoma cells more efficiently than K274Q tau. The results indicated that the acetylation of K274 residue of tau may increase metal ion-induced toxicity and diminish the ability of tau to protect DNA.

中文翻译：

---

乙酰基模拟突变，Tau中的K274Q，增强了Tau的金属结合亲和力，并降低了Tau保护DNA的能力。

已知tau（一种微管相关蛋白）的聚集在包括阿尔茨海默氏病在内的多种神经系统疾病中起着重要作用。阿尔茨海默氏病被认为与金属离子（如铝，锌，铜和铁离子）的动态平衡不良有关。在阿尔茨海默氏病中，Tau主要在K274残基处被乙酰化，而K274残基的乙酰化被认为与痴呆症有关。使用tau中的乙酰基模拟K274Q突变，我们检查了tau的K274残基处的乙酰化对tau与金属离子的相互作用以及tau保护DNA免受热和其他胁迫的能力的影响。我们发现Zn2 +和Al3 +增加了tau的液-液相分离，这是tau聚集的初始阶段。进一步，Zn2 +和Al3 +大大降低了K274Q tau相分离的临界浓度。使用远紫外圆二色性和荧光光谱法，我们提供的证据表明Zn2 +和Al3 +的结合会诱导tau的构象变化。K274Q突变增强了tau对Zn2 +，Al3 +，Cu2 +和Fe3 +离子的结合亲和力。此外，与tau相比，Zn2 +，Al3 +，Cu2 +和Fe3 +显着增强了K274Q tau的聚集倾向。有趣的是，tau以比K274Q tau更高的亲和力与DNA结合。与K274Q tau相比，Tau可以更有效地保护DNA免受DNase的体外处理以及神经母细胞瘤细胞的热应激。结果表明，tau K274残基的乙酰化作用可能会增加金属离子诱导的毒性，并降低tau保护DNA的能力。