C-H ... π interplay between Ile308 and Tyr310 residues in the third repeat of microtubule binding domain is indispensable for self-assembly of three- and four-repeat tau

• Published in: Journal of biochemistry (Tokyo) Vol. 152; no. 3; p. 221
• Main Authors: Sogawa, Koushirou, Okuda, Ryouhei, In, Yasuko, Ishida, Toshimasa, Taniguchi, Taizo, Minoura, Katsuhiko, Tomoo, Koji
• Format: Journal Article
• Language: English
• Published: England 01.09.2012
• Subjects: Amino Acid Sequence; Circular Dichroism; Fluorescence; Humans; Isoleucine - metabolism; Microtubules - metabolism; Models, Molecular; Molecular Sequence Data; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutant Proteins - ultrastructure; Protein Binding; Protein Structure, Quaternary; Protein Structure, Tertiary; Reducing Agents - pharmacology; Repetitive Sequences, Amino Acid; Structure-Activity Relationship; tau Proteins - chemistry; tau Proteins - metabolism; tau Proteins - ultrastructure; Time Factors; Tyrosine - metabolism
• ISSN: 1756-2651; 1756-2651
• DOI: 10.1093/jb/mvs061

Information on the structural scaffold for tau aggregation is important in developing a method of preventing Alzheimer's disease (AD). Tau contains a microtubule binding domain (MBD) consisting of three or four repeats of 31 and 32 similar residues in its C-terminal half. Although the key event in tau aggregation has been considered to be the formation of β-sheet structures from a short hexapeptide (306)VQIVYK(311) in the third repeat of MBD, its aggregation pathway to filament formation differs between the three- and four-repeated MBDs, owing to the intermolecular and intramolecular disulphide bond formations, respectively. Therefore, the elucidation of a common structural element necessary for the self-assembly of three-/four-repeated full-length tau is an important research subject. Expanding the previous results on the aggregation mechanism of MBD, in this paper, we report that the C-H … π interaction between the Ile308 and Tyr310 side chains in the third repeat of MBD is indispensable for the self-assembly of three-/four-repeated full-length tau, where the interaction provides a conformational seed for triggering the molecular association. On the basis of the aggregation behaviours of a series of MBD and full-length tau mutants, a possible self-association model of tau is proposed and the relationship between the aggregation form (filament or granule) and the association pathway is discussed.