Tau protein regulates, maintains and stabilizes microtubule assembly under normal physiological conditions. In certain pathological circumstances, tau is post-translationally modified predominantly via phosphorylation and glycosylation. Hyper-phosphorylation of tau in Alzheimer’s disease (AD) resulted in aggregated neurofibrillary tangles (NFTs) formation. Unfortunately, absence of tau 3D structure makes difficult to understand exact mechanism involved in tau pathology. Here by using ab-initio modelling, we predicted a tau 3D structure that not only explains its binding with microtubules but also elucidates NFTs formation. O-linked β-N-acetylglucosaminylation (O-β-GlcNAc) is thought to regulate tau phosphorylation on single or proximal Ser/Thr residues (called as Yin-Yang sites). In this study, we not only validate the previously described three-serine residues (208, 238 and 400) as Yin-Yang sites but also predicted 22 more possible Ser/Thr O-glycosylation sites. Among them seventeen residues were predicted as possible Yin-Yang sites and are proposed to mediate NFT formation in AD. These predicted Yin-Yang sites may act as attractive therapeutic targets for the drug development in AD. Predicted 3D structure of tau₄₄₁ was highly accessible for phosphorylation and hyperphosphorylation, and showed higher surface accessibility for interplay between O-β-GlcNAc and phosphorylation modifications. Kinases and phosphatases involved in tau phosphorylation are conserved in human and other organisms. Homology modelling revealed conserved catalytic domain for both human and C. elegans O-GlcNAc transferase (OGT), suggesting that transgenic C. elegans expressing human tau may be a suitable model system to study these modifications.

Tau蛋白在正常生理条件下调节，维持和稳定微管组装。在某些病理情况下，tau主要通过磷酸化和糖基化进行翻译后修饰。阿尔茨海默氏病（AD）中tau的过度磷酸化导致聚集的神经原纤维缠结（NFTs）形成。不幸的是，缺少tau 3D结构使得难以理解tau病理学所涉及的确切机制。在这里，通过使用从头开始建模，我们预测了tau 3D结构，该结构不仅解释了其与微管的结合，而且阐明了NFT的形成。ø -连接的β- Ñ -acetylglucosaminylation（Ô（β-GlcNAc）被认为可调节单个或近端Ser / Thr残基（称为阴阳位点）上的tau磷酸化。在这项研究中，我们不仅验证了先前描述的三个丝氨酸残基（208、238和400）作为阴阳位点，而且还预测了22个可能的Ser / Thr O-糖基化位点。其中17个残基被预测为可能的阴阳位点，并被提议介导AD中NFT的形成。这些预测的阴阳位点可以作为AD中药物开发的有吸引力的治疗靶标。预测的tau _441的3D结构对于磷酸化和超磷酸化非常容易接近，并且对于O之间的相互作用显示更高的表面可达性-β-GlcNAc和磷酸化修饰。涉及tau磷酸化的激酶和磷酸酶在人类和其他生物中是保守的。同源性建模揭示了人和秀丽隐杆线虫O- GlcNAc转移酶（OGT）的保守催化结构域，表明表达人tau的转基因秀丽隐杆线虫可能是研究这些修饰的合适模型系统。