title: CH-π interaction in VQIVYK sequence elucidated by NMR spectroscopy is essential for PHF formation of tau.
abstract: One of the histopathological features of Alzheimer's disease (AD) is higher order neurofibrillary tangles formed by abnormally aggregated tau protein. Investigation of the mechanism of tau aggregation is important for the clarifying the cause of AD and the development of therapeutic drugs. The microtubule-binding domain, which consists of repeats of similar amino acids (R1-R4) is thought to form the core component of paired helical filament (PHF). The hexapeptide(306) VQIVYK(311) of R3 has been shown to take a key role of promoting tau aggregation and assumed that its CH-π interaction between the side chains of Ile308 and Tyr310 would contribute in stabilizing the filament. In this work, we investigated a short isoform of tau (4RTau), R3, VQIVYK peptide and their mutants by thioflavin S (ThS) fluorescence, and NMR measurements, and proved for the first time that this CH-π interaction stabilizes the filament at the atomic level. In addition, by molecular modeling, we revealed that this interaction further supports an extended amphipathic structure for molecular self-association during the process of PHF formation of tau protein. The present work indicates new approach that inhibits the CH-π interaction for developing a therapeutic agent for AD.
authors.affiliation: Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Osaka, 569-1094, Japan.
authors.forename: Koushirou
authors.initials: K
authors.lastname: Sogawa
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Minoura
authors.forename: Yasuko
authors.initials: Y
authors.lastname: In
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishida
authors.forename: Taizo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D052160:Benzothiazoles; D005453:Fluorescence; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D050505:Mutant Proteins; D010455:Peptides; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T
keywords: CH-π interaction; NMR spectroscopy; tau protein