BACKGROUND Various neurodegenerative diseases, including Alzheimer's disease (AD), are related to abnormal hyperphosphorylated microtubule-associated protein tau accumulation in brain lesions. Recent studies have focused on toxicity caused by another post-translational modification (PTM), acetylation of the lysine (K) residues of tau protein. Because there are numerous acetylation sites, several studies have introduced mimics of tau acetylation using amino acid substitutions from lysine to glutamine (Q). However, human tau protein contains over 20 acetylation sites; thus, investigation of the effects of an acetylated tau is difficult. OBJECTIVE Here, the authors in silico evaluated acetylation effects using SIFT, PolyPhen-2 and PROVEAN which can estimate the effects of amino acid substitutions based on the sequence homology or protein structure in tau isoforms. In addition, they also investigated 27 acetylation effects on the amyloid formation of tau proteins using Waltz. RESULTS 15 acetylation mimics were estimated to be the most detrimental, which indicates that there may be novel pathogenic acetylation sites in the human tau protein. Interestingly, the deleterious effect of acetylation mimics was different according to the type of isoforms. Furthermore, all acetylation mimics were predicted to be a region of amyloid formation at the codons 274-279 of human tau protein. Notably, acetylation mimic of codon 311 (K311Q) induced the formation of an additional amyloid region located on codons 306-311 of the human tau protein. CONCLUSION To the best of our knowledge, this is the first simultaneous in-silico evaluation of the acetylation state of 27 human tau protein residues.

中文翻译：

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在计算机模拟评估人类Tau蛋白的27个赖氨酸残基中的乙酰化模拟物。

背景技术各种神经退行性疾病，包括阿尔茨海默氏病（AD），与脑损伤中异常的高磷酸化微管相关蛋白tau蓄积有关。最近的研究集中于由另一种翻译后修饰（PTM）引起的毒性，tau蛋白的赖氨酸（K）残基被乙酰化。因为有许多乙酰化位点，所以一些研究已经引入了tau乙酰化的模拟物，使用从赖氨酸到谷氨酰胺（Q）的氨基酸取代。但是，人tau蛋白含有20多个乙酰化位点；因此，难以研究乙酰化tau的作用。目的在这里，计算机科学作者使用SIFT评估了乙酰化作用，PolyPhen-2和PROVEAN可以根据tau亚型的序列同源性或蛋白质结构估算氨基酸取代的影响。此外，他们还使用Waltz研究了27种乙酰化作用对tau蛋白淀粉样蛋白形成的影响。结果估计有15种乙酰化模拟物是最有害的，这表明人tau蛋白中可能存在新的致病性乙酰化位点。有趣的是，乙酰化模拟物的有害作用根据同工型的类型而不同。此外，所有乙酰化模拟物都被认为是人tau蛋白密码子274-279处淀粉样蛋白形成的区域。值得注意的是，密码子311（K311Q）的乙酰化模拟诱导了位于人tau蛋白密码子306-311上的另一个淀粉样蛋白区域的形成。