title: Peptidyl-prolyl isomerase activity of FK506 binding protein 12 prevents tau peptide from aggregating.
abstract: The Alzheimer's disease-related protein, tau, aggregates into neurofibrillary tangles when it is hyperphosphorylated. The amino acid sequence included in the third repeat (R3) of the microtubule-binding region is suspected to be the main factor for tau aggregation. Here, we synthesized a 31-residue oligopeptide, corresponding to the R3 region, and characterized its aggregation propensity under various conditions. This peptide aggregated even in the absence of an aggregation-inducing molecule at a low salt concentration, while it did not form any aggregates at a high salt concentration. This suggests that hydrophilic interactions are the main cause of aggregation. We then investigated the function of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggregation of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1 : 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states.
authors.affiliation: Laboratory of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. ikura.str@tmd.ac.jp
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005427:Flocculation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D019696:Peptidylprolyl Isomerase / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry* / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D010455:Peptides; D012996:Solutions; D016875:tau Proteins; D022061:Tacrolimus Binding Protein 1A; D019696:Peptidylprolyl Isomerase
keywords: Alzheimer's disease; FK506 binding protein 12; neurofibrillary tangles; peptidyl-prolyl isomerase activity; tau protein