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

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.