title: Linkage-dependent contribution of repeat peptides to self-aggregation of three- or four-repeat microtubule-binding domains in tau protein.
abstract: Although one of the priorities in Alzheimer's research is to clarify the filament formation mechanism for the tau protein, it is still unclear how it is transformed from a normal structure in a neuron. To examine the linkage-dependent contribution of each repeat peptide (R1-R4) to filament formation of the three- or four-repeat microtubule-binding domain (MBD) in the tau protein, four two-repeat peptides (R12, R13, R23 and R34) and two three-repeat peptides (R123 and R234) were prepared, and their in vitro self-aggregation was investigated by thioflavin S fluorescence and circular dichroism measurements, and by electron microscopy in neutral buffer (pH 7.6). Comparison of these aggregation behaviors with previous results for single-repeat peptides and wild-type 3RMBD (R134) and 4RMBD (R1234) indicated that (a) the two-repeat R23, not the R2 or R3 single repeat, forms the core structure in self-aggregation of 4RMBD, whereas that of 3RMBD comprises the R3 single repeat, (b) co-existence of R1 and R4 repeats is necessary for the aggregation behavior inherent in 3RMBD and 4RMBD, whereas the R1 or R4 repeat alone functions as a repressor or modifier of the filament formation, (c) 4RMBD aggregation is accompanied by R1-driven transition from random and alpha-helix structures to a beta-sheet structure, whereas 3RMBD aggregation involves three-repeat R134-specific transition from a random structure to an alpha-helix structure without the participation of a beta-sheet structure, and (d) the peptides that include the R1 repeat form a long filament irrespective of the absence or presence of the R4 repeat, whereas those that include the R4 repeat, but not the R1 repeat, form a relatively short filament. To the best of our knowledge, a systematic study of the linkage-dependent contribution of each repeat peptide to the paired helical filament formation of tau MBD has not been carried out previously, and thus the present information is useful for understanding the essence of the filament formation of tau MBD.
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Okuyama
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Nishiura
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Mizushima
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Minoura
authors.affiliation:  Behavioral and Medical Sciences Research Consortium, Akashi, Hyogo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Sumida
authors.affiliation:  Behavioral and Medical Sciences Research Consortium, Akashi, Hyogo, Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tomoo
authors.affiliation:  Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishida
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D006493:Heparin / Q000502:physiology; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020449:Repetitive Sequences, Amino Acid; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D016875:tau Proteins; D006493:Heparin