title: Insight into potential Cu(II)-binding motifs in the four pseudorepeats of tau protein.
abstract: Tau protein and Cu(II) are believed to be associated with the pathogenesis of Alzheimer's disease. However, little is known about atomic-level interactions between tau protein and Cu(II). Herein, we suggest, on the basis of electron spin resonance (ESR) data, that the four pseudorepeats of tau protein in the microtubule-binding region play an important role in Cu(II) binding. We use a number of tau protein fragments in order to examine Cu(II)-binding site(s) and binding affinities. Continuous-wave (CW) ESR experiments on the four highly conserved octadecapeptides, each of which is a segment of one of the four pseudorepeats, reveal that the equimolar Cu(II) complexes of the four octadecapeptides are similar to one another in terms of the coordination environment and binding affinity. The spectra obtained with pulsed ESR techniques such as electron spin-echo envelope modulation and hyperfine sublevel correlation provide direct evidence that a histidine residue and a backbone amide group coordinate to Cu(II) in each Cu(II)-octadecapeptide complex. The results of CW and pulsed ESR experiments on some chemically modified peptides indicate that the cysteine residues in the second and third pseudorepeats are unlikely to be involved in Cu(II) binding. On the other hand, similar experiments on tau fragments of the second pseudorepeat with different lengths lead to the conclusion that the affinity for Cu(II) decreases as the octadecapeptide is either truncated or elongated. The high Cu(II)-binding affinity of the octadecapeptide is presumably due to the N-terminal amino group stabilizing the Cu(II)-octadecapeptide complex. Finally, the ESR data for a longer tau fragment that contains two octadecapeptides suggest that the Cu(II) binding site(s) of even longer fragments of tau protein is similar to that of a single octadecapeptide.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Byong-kyu
authors.initials: BK
authors.lastname: Shin
authors.forename: Sunil
authors.initials: S
authors.lastname: Saxena
mesh_terms: D000577:Amides / Q000737:chemistry; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D003300:Copper / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006639:Histidine; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020449:Repetitive Sequences, Amino Acid; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000577:Amides; D010446:Peptide Fragments; D016875:tau Proteins; D006639:Histidine; D003300:Copper