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.
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.
Department of Physical Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-11, Japan.
Koushirou
K
Sogawa
Ryouhei
R
Okuda
Yasuko
Y
In
Toshimasa
T
Ishida
Taizo
T
Taniguchi
Katsuhiko
K
Minoura
Koji
K
Tomoo
D000595:Amino Acid Sequence; D002942:Circular Dichroism; D005453:Fluorescence; D006801:Humans; D007532:Isoleucine / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D019163:Reducing Agents / Q000494:pharmacology; D020449:Repetitive Sequences, Amino Acid; D013329:Structure-Activity Relationship; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D050505:Mutant Proteins; D019163:Reducing Agents; D016875:tau Proteins; D007532:Isoleucine; D014443:Tyrosine