Importance of Tyr310 residue in the third repeat of microtubule binding domain for filament formation of tau protein

The inhibition of tau fibrillation is a potential therapeu-tic target for Alzheimer’s and other neurodegenerative diseases. As a series of studies on inhibiting the transi-tion of soluble monomeric tau into mature fibril, the effect of Tyr310 residue in the third repeat (R3) of the microtubule-binding domain (MBD) on the assem-bly of MBD was investigated using Tyr-substituted MBD mutants by fluorescence, circular dichroism spec-troscopy and electron microscopy. Consequently, the importance of the Tyr residue located at position 310, not at other positions, was clearly shown. The confor-mational comparison of the Tyr310Ala-substituted R3 repeat peptide with the unsubstituted one showed that the Tyr residue contributes to the rigid extended struc-ture of the N-terminal V306QIVYK311 sequence, and its replacement by Ala leads to the deformation of the extended structure, consequently losing its aggregation ability. The present results indicate that a compound that interacts specifically with the Tyr residue or an antibody recognizing the region containing the Tyr res-idue becomes a candidate for inhibiting tau fibrillation