Thermodynamics and structural characterization of the nickel(II) and zinc(II) complexes of various peptide fragments of tau protein

Abstract

Nickel(II) and zinc(II) complexes of various peptide fragments of tau protein have been investigated by potentiometric, UV-Vis, CD and ESI-MS techniques. The peptides include the native fragment tau(9-16) (Ac-EVMEDHAG-NH₂), and the Gln/Lys and Tyr/Ala mutated peptides (Ac-KGGYTMHK-NH₂ and Ac-KGGATMHK-NH₂) of tau(26-33). Similar to copper(II) the complexes of a chimeric peptide containing both His14 and His32 residues in one molecule (Ac-EDHAGTMHQD-NH₂) were also studied. The metal binding ability of the R3 domain was studied by using the native fragment tau(326-333) (Ac-GNIHHKPG-NH₂), and its two mutants (Ac-GNIHHKAG-NH₂) and (Ac-GNGHHKPG-NH₂) and the corresponding 1-histidine mutants (Ac-GNGAHKPG-NH₂ and Ac-GNGHAKPG-NH₂). The results of this study reveal that the histidyl residues of the N-terminal and R3 regions of tau protein can effectively bind nickel(II) and zinc(II) ions. In the case of nickel(II) and zinc(II) the M-N_im coordinated complexes are the major species in the physiological pH range and their stability is significantly enhanced by the presence of Glu and Asp residues in the neighbourhood of the His14 site. For all studied peptides, nickel(II) ions are able to promote the deprotonation and coordination of amide groups preceding histidine resulting in the exclusive formation of square planar (N_im,3N^-) complexes in alkaline solutions. The native fragment of the R3 region and its mutants containing two adjacent histidine moieties also bind only one nickel(II) ion with the His330 residue being the primary metal binding site. Exclusive binding of the independent imidazole side chains (His14 and His32 sites) cannot prevent the hydrolysis of zinc(II) in a slightly basic solution but the adjacent histidines of the R3 domain can promote the formation of amide coordinated zinc(II) complexes.