A comprehensive study of the role of phosphorylation in the coordination and hydrolytic behaviour of the human tau(28-34) protein fragment

Phosphorylation of tau protein by kinases is an abnormal biological process that can significantly alter the chemical properties and conformation of the protein. However, in the context of Alzheimer’s disease (AD), phosphorylation may play an important role in protein aggregation and the development of neurodegenerative diseases. Literature data have demonstrated that potential phosphorylation of the alcoholic side chains of threonyl and seryl residues in the tau protein sequence has a significant impact on the accumulation of the protein. The present article investigates the role of phosphorylation of the threonyl residue in the -TMH- motif in the human tau(28–34) protein fragment, in the chemical interaction of the tau peptide with metal ions. The interaction of the native tau(28–34) protein fragment (Ac-GYTMHQD-NH ₂ ), as well as the phosphorylated tau(28-30T(P)-34) peptide (Ac-GYT(P)MHQD-NH ₂ ), with essential Cu(II), Zn(II), and toxic Ni(II) ions has been thoroughly investigated. Thermodynamic equilibrium studies have shown that phosphorylation of threonine considerably improves metal ion binding affinity and increases the stability constants of M(II)-N _im complexes. Furthermore, there were unambiguous differences in the CD and UV-Vis spectra of Cu(II) and Ni(II) complexes compared to those of the native tau peptide complexes. The hydrolytic stability of the amide bond between tyrosyl and threonyl residues was investigated for the native peptide in the presence of Ni(II) at 25°C and different pH values. However, the irreversible hydrolytic reaction was inhibited in the case of the phosphorylated tau peptide.