Zn2+ Interrupts R4‐R3 Association Leading to Accelerated Aggregation of Tau Protein

• Published in: Chemistry : a European journal 2017-12, Vol.23 (67), p.16976-16979
• Main Authors: Jiji, A. C., Arshad, A., Dhanya, S. R., Shabana, P. S., Mehjubin, C. K., Vijayan, Vinesh
• Format: Article
• Language: English
• Subjects: Agglomeration; Alzheimer's disease; Binding; Chemistry; Molecular interactions; NMR; NMR spectroscopy; non-covalent interactions; Nuclear magnetic resonance; Peptides; Tau protein; Toxicity; Zinc
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201704555

Direct binding of divalent metal ion, especially Zn2+, have been shown to increase the rate of tau aggregation and enhance tau toxicity in cells. Hence, understanding the molecular basis of the Zn2+‐accelerated tau aggregation can potentially determine the molecular interactions modulating tau aggregation. Herein, we show that Zn2+ coordinates through the cysteine in R3 repeat and significantly accelerates the aggregation rate of the three repeat tau constructs (K19) but that the coordination is incapable of increasing the aggregation rate of the 20 amino acid peptide derived from the R3 repeat (R3) of tau. The NMR characterization of the binding of Zn2+ to K19, together with the aggregation studies with K19, R3 and R4 peptides, reveal the presence of an aggregation‐inhibitory interaction between the R3 and R4 repeat of K19. Our data show that binding of Zn2+ to R3 repeat of tau, weaken the aggregation‐inhibiting influence between R3 and R4 repeats, leading to faster aggregation of tau protein. Blocking their neighbour: The three repeat tau exist in an aggregation‐inhibitory conformation with residues in R4 repeat preventing the R3 repeat from aggregation. The binding of ZnII to the R3 repeat weakens the inhibitory effect of R4 and accelerate the aggregation of tau protein.