Possible phosphorylation code for the fibril formation of tau protein

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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.