How copper(II) and zinc(II) bind to Tau protein and how might this promote aggregation?

Abstract

Neurodegenerative taupathies are characterized by extracellular protein deposits of amyloid-β and intracellular aggregates of hyperphosphorylated tau in the brain. Great number of publications supports that essential metal ions (such as zinc and copper) play an important role in the development of neurodegeneration. The histidine imidazole rings are frequent metal binding sites in proteins and tau is relatively rich in this moiety. The 12 histidyl residues of the protein are well-separated and can be found in different chemical environment, hence their metal binding properties – at least slightly – differ. The comparison of the metal binding affinity of the His32 moiety from the N-terminal part of tau and the His329-His330 residues derived from the R3 domain revealed that copper(II) binding is more favourable to His32 than metal coordination by the adjacent imidazoles; while the His329-His330 moieties provide a binding site for zinc(II) ions at physiological pH. To further elucidate the metal binding ability of His32 and His329-His330 we studied the complex formation processes of a chimeric peptide (Ac-TMHQDNIHHKP-NH2) that contains the 30-34 residues (TMHQD) linked to the 327-332 residues (NIHHKP) in a single molecule (tau(30-34)(327-332)). The pH potentiometric, spectroscopic (UV-Vis, CD) and mass spectrometry studies on the copper(II) complexes of the peptide revealed that in equimolar samples predominantly mononuclear complexes with 1:1 stoichiometry are formed. At physiological pH and in alkaline samples the His32 imidazole nitrogen becomes the main, albeit not exclusive, anchoring group. The coordination mode of these copper(II) complexes can be described with the involvement of imidazole-N donor atoms and deprotonated amide functions. In the presence of zinc(II) ions only mononuclear species are formed. The results obtained for the mixed copper(II)-zinc(II) complexes support that the N-terminal imidazole nitrogen (His32) is the main anchoring group for copper(II) ions, while zinc(II) is accumulated at one of the adjacent histidyl residues if both metal ions are present in the solution at physiological pH. These findings are in agreement with the hypothesis that zinc(II), by binding to the R3 region, aggravate the aggregation processes of the R3 region and may increase the tau's toxicity.