Nickel(II) and Zinc(II) Binding to Tau Protein Fragments Containing Histidine and Cysteine

Abstract Tau protein plays a crutial role in stablizing the neuronal microtubules in the human brain, under normal physiological environment. This protein contains 12 histidines and 2 cysteines, which are typically the primary metal binding sites. As the metal ions may participate in tau protein aggregation processes and the development of taupathies, we characterized zinc(II) and nickel(II) complexes of tau fragments. The studied peptides were; single-His299 containing tau(292–301) (Ac-GSKDNIKHVP-NH 2 ) and its asparagine mutant at position 300, tau(288–293) (Ac-QSKCGS-NH 2 ) and tau(289–292) (Ac-SKCG-NH 2 ) containing only Cys291, as well as tau(289-V300N) (Ac-SKCGSKDNIKHN-NH 2 ) containing both Cys291 and His299. The pH potentiometric, UV-visible and CD spectroscopic measurements allowed us to understand the effect of these side chains on the stability and binding mode of metal ion complexes. For peptides containing a single cysteine and single histidine, nickel(II) complexes with (N – ,N – ,N – ,S – ) and (N – ,N – ,N – ,N Im ) coordination modes were main species in alkaline media. UV-visible and CD spectroscopic curves showed that nickel(II) favours the cysteine binding site in the case of the tau(289–300) fragment. Through the bidentate coordination of this tau peptide, the stability of zinc(II) complex is significantly increased compared to fragments containing a single binding site.