title: Importance of Tyr310 residue in the third repeat of microtubule binding domain for filament formation of tau protein.
abstract: The inhibition of tau fibrillation is a potential therapeutic target for Alzheimer's and other neurodegenerative diseases. As a series of studies on inhibiting the transition 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 assembly of MBD was investigated using Tyr-substituted MBD mutants by fluorescence, circular dichroism spectroscopy and electron microscopy. Consequently, the importance of the Tyr residue located at position 310, not at other positions, was clearly shown. The conformational comparison of the Tyr310Ala-substituted R3 repeat peptide with the unsubstituted one showed that the Tyr residue contributes to the rigid extended structure of the N-terminal V(306)QIVYK(311) 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 residue becomes a candidate for inhibiting tau fibrillation.
authors.affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nishiura
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Minoura
authors.forename: Miho
authors.initials: M
authors.lastname: Sumida
authors.forename: Taizo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016874:Neurofibrillary Tangles / Q000737:chemistry*; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D014443:Tyrosine / Q000737:chemistry*; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D016875:tau Proteins; D014443:Tyrosine