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CH-π interaction in VQIVYK sequence elucidated by NMR spectroscopy is essential for PHF formation of tau.
Sogawa, Koushirou; Minoura, Katsuhiko; In, Yasuko; Ishida, Toshimasa; Taniguchi, Taizo; Tomoo, Koji.
Afiliación
  • Sogawa K; Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, Osaka, 569-1094, Japan.
Biopolymers ; 102(3): 288-95, 2014 May.
Article en En | MEDLINE | ID: mdl-24687309
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Resonancia Magnética Nuclear Biomolecular Tipo de estudio: Prognostic_studies Idioma: En Revista: Biopolymers Año: 2014 Tipo del documento: Article País de afiliación: Japón

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Resonancia Magnética Nuclear Biomolecular Tipo de estudio: Prognostic_studies Idioma: En Revista: Biopolymers Año: 2014 Tipo del documento: Article País de afiliación: Japón
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