Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

Copper(II) complexes of the N‐terminal peptide fragments of tau protein have been studied by potentiometric and various spectroscopic techniques (UV‐vis, CD, ESR and ESI‐MS). The octapeptide Tau(9‐16) (Ac−EVMEDHAG−NH2) contains the H14 residue of the native protein, while Tau(26‐33) (Ac−QGGYTMHQ−NH2) and its mutants Tau(Q26K‐Q33K) (Ac−KGGYTMHK−NH2) and Tau(Q26K‐Y29A‐Q33K) (Ac−KGGATMHK−NH2) include the H32 residue. To compare the binding ability of H14 and H32 in a single molecule the decapeptide Ac−EDHAGTMHQD−NH2 (Tau(12‐16)(30‐34)) has also been synthesized and studied. The histidyl residue is the primary metal binding site for metal ions in all the peptide models studied. In the case of Tau(9‐16) the side chain carboxylate functions enhance the stability of the M−Nim coordinated complexes compared to Tau(26‐33) (logK(Cu−Nim)=5.04 and 3.78, respectively). Deprotonation and metal ion coordination of amide groups occur around the physiological pH range for copper(II). The formation of the imidazole‐ and amide‐coordinated species changes the metal ion preference and the complexes formed with the peptides containing the H32 residue predominate over those of H14 at physiological pH values (90 %–10 %) and in alkaline samples (96 %–4 %). Plan well before binding: Studies on the N‐terminal part of the tau protein reveal that the His32 is the preferred binding site over His14 for copper(II) at both physiological and alkali pH values. This is well demonstrated in the diagram which shows the ratio of free copper(II), the copper(II) complexes of Tau(9‐16) and Tau(26‐33) in the model system containing copper(II)−Tau(9‐16)−Tau(26‐33) in equimolar amount at different pH.