Abstract
The tau protein plays an important role in some neurodegenerative diseases including Alzheimer's disease (AD). Neurofibrillary tangles (NFTs), a biological marker for AD, are aggregates of bundles of paired helical filaments (PHFs). In general, the α‐sheet structure favors aberrant protein aggregates. However, some reports have shown that the α‐helix structure is capable of triggering the formation of aberrant tau protein aggregates and PHFs have a high α‐helix content. In addition, the third repeat fragment in the four‐repeat microtubule‐binding domain of the tau protein (residues 306–336: VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQ, according to the longest tau protein) adopts a helical structure in trifluoroethanol (TFE) and may be a self‐assembly model in the tau protein. In the human brain, there is a very small quantity of copper, which performs an important function. In our study, by means of matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI‐TOF MS), circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy, the binding properties of copper (II) ion to the R3 peptide derived from the third repeat fragment (residues 318–335: VTSKCGSLGNIHHKPGGG) have been investigated. The results show that copper ions bind to the R3 peptide. CD spectra, ultraviolet (UV)‐visible absorption spectra, and MALDI‐TOF MS show pH dependence and stoichiometry of Cu^2+^ binding. Furthermore, CD spectra and NMR spectroscopy elucidate the copper binding sites located in the R3 peptide. Finally, CD spectra reveal that the R3 peptide adopts a mixture structure of random structures, α‐helices, and β‐turns in aqueous solutions at physiological pH. At pH 7.5, the addition of 0.25 mol eq of Cu^2+^ induces the conformational change from the mixture mentioned above to a monomeric helical structure, and a β‐sheet structure forms in the presence of 1 mol eq of Cu^2+^. As α‐helix and β‐sheet structures are responsible for the formation of PHFs, it is hypothesized that Cu^2+^ is an inducer of self‐assembly of the R3 peptide and makes the R3 peptide form a structure like PHF. Hence, it is postulated that Cu^2+^ plays an important role in the aggregation of the R3 peptide and tau protein and that copper (II) binding may be another possible involvement in AD. © 2005 Wiley Periodicals, Inc. Biopolymers 79: 74–85, 2005
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