Possible phosphorylation code for the fibril formation of tau protein

过度磷酸化形式的tau蛋白是阿尔茨海默病患者大脑中神经原纤维缠结的成对螺旋丝（phf）的主要成分。然而，个体磷酸化事件如何诱导phf形成的详细机制仍有待确定。Tau衍生的磷酸化肽已被用于了解磷酸化对Tau蛋白纤颤的影响，并首次证明了带电残基的位置对Tau蛋白淀粉样蛋白纤颤起着关键作用。我们研究了tau蛋白的原纤维形成序列VQIVYK (PHF6)，该序列在tau蛋白的天然同工异构体的n端含有丝氨酸或赖氨酸，并合成了PHF6衍生的磷酸化丝氨酸和/或酪氨酸肽。有趣的是，与具有相同净电荷的酪氨酸磷酸化肽相比，在n端丝氨酸残基磷酸化的肽显示出明显低的纤颤倾向。我们的结果表明，过度磷酸化对tau蛋白原纤维形成的作用不应该仅仅从改变蛋白净电荷的角度来考虑。磷酸化将提供tau蛋白的许多变异，这些变异可以定义淀粉样蛋白型纤维形成的“tau蛋白磷酸化代码”。

Hyperphosphorylated forms of tau protein are the main component of paired helical filaments (PHFs) of neurofibrillary tangles inthe brain of Alzheimer’s disease patient. However, the detailed mechanisms of how the individual phosphorylation event induces the formation of PHFs remain to beestablished. Tau derived phosphorylated peptides have been utilized to understand the effect of phosphorylation on fibrillation of tau and showed the first example that the position of charged residue plays a critical role for the amyloid fibrillation of tau. We have focused on the fibril-forming sequence of tau, VQIVYK (PHF6), that possesses serine or lysine at its N-terminal in the native isoform of tau, and synthesized the PHF6 derived phosphorylated serine and/or tyrosine containing peptide. Interestingly, the peptide phosphorylated at the N-terminal serine residue showed remarkably low fibrillation propensity as compared to the peptide phosphorylated at tyrosine that possessed the same net-charge. Our results indicate that the role of hyperphosphorylation for the fibril formation of tau should not be considered only from the point of view of altering the net charge of protein. The phosphorylation would afford many variation of tau that could define a "tau-phosphorylation code" for the amyloid-type fibril formation.