title: Structural evaluation of conformational transition state responsible for self-assembly of tau microtubule-binding domain.
abstract: In the brains of Alzheimer's disease patients, the tau protein abnormally aggregates to form an insoluble paired helical filament (PHF). Since the third repeat structure (R3) of the tau microtubule-binding domain plays an essential role in PHF formation and self-aggregates most significantly in an aqueous solution of 20-40% trifluoroethanol (TFE), its possible conformation was estimated from the combination of (i) the TFE-dependent deviations of NH and CalphaH proton chemical shifts from those of the random structure in water and (ii) the TFE-dependent NOE effect connectivity diagrams between the neighboring protons. Consequently, it was indicated that the extended structure of the N-terminal VQIVYK moiety and the alpha-helical-like structure of the LSKVTSKC region provide a structural scaffold for initiating the self-assembled filament formation of the R3 structure. To the best of our knowledge, this is the first study that demonstrated the initial structural moiety and its structural feature necessary for starting the tau PHF formation.
authors.affiliation: Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. minoura@gly.oups.ac.jp
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Minoura
authors.forename: Fumie
authors.initials: F
authors.lastname: Mizushima
authors.forename: Mari
authors.initials: M
authors.lastname: Tokimasa
authors.forename: Shuko
authors.initials: S
authors.lastname: Hiraoka
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
authors.forename: Miho
authors.initials: M
authors.lastname: Sumida
authors.forename: Taizo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D011522:Protons; D016415:Sequence Alignment; D014270:Trifluoroethanol; D014867:Water; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000577:Amides; D011522:Protons; D016875:tau Proteins; D014867:Water; D014270:Trifluoroethanol