Possible phosphorylation code for the fibril formation of tau protein

tau蛋白的过度磷酸化形式是阿尔茨海默病患者脑内神经元缠结的成对螺旋丝（PHF）的主要成分。然而，磷酸化事件如何诱导PHFs形成的详细机制仍有待建立。Tau衍生的磷酸化肽已被用于理解磷酸化对Tau纤维化的影响，并显示了带电残基的位置对Tau的淀粉样纤维化起关键作用的第一个例子。我们已经集中在纤维形成序列的tau，VQIVYK（PHF 6），具有丝氨酸或赖氨酸在其N-末端的天然同种型的tau，并合成PHF 6衍生的磷酸化丝氨酸和/或酪氨酸含有肽。有趣的是，与具有相同净电荷的酪氨酸磷酸化的肽相比，在N-末端丝氨酸残基磷酸化的肽显示出显著低的原纤化倾向。我们的研究结果表明，过度磷酸化的tau蛋白原纤维形成的作用不应该被认为只是从改变蛋白质的净电荷的角度来看。磷酸化将提供tau的许多变化，这些变化可以定义淀粉样蛋白型原纤维形成的“tau磷酸化密码”。

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.