Sequential binding of zinc triggers tau aggregation

Abstract

Tau protein has been extensively studied due to its key roles in microtubular cytoskeleton regulation and in the formation of aggregates found in some neurodegenerative diseases. Recently it has been shown that zinc is able to induce tau aggregation by interacting with several binding sites. However, the precise location of these sites and the molecular mechanism of zinc-induced aggregation remain unknown. Here we used Nuclear Magnetic Resonance (NMR) to identify zinc binding sites on hTau40 isoform. These experiments revealed three distinct zinc binding sites on tau, located in the N-terminal part (H14, H32, H94, and H121), the repeat region (H299, C322, H329 and H330) and the C-terminal part (H362, H374, H388 and H407). Further analysis enabled us to show that the C-terminal and the N-terminal sites are independent of each other. Using molecular simulations, we modeled the structure of each site in a complex with zinc. Given the clinical importance of zinc in tau aggregation, our findings pave the way for designing potential therapies for tauopathies. HighlightsO_LIZinc is known to induce tau aggregation in neurodegenerative diseases C_LIO_LIZinc binding locations and mechanism are not yet clear C_LIO_LIUsing NMR we localized 3 zinc binding site on tau C_LIO_LIBy molecular simulations, we proposed a modeled structure of each site C_LIO_LIOur findings pave the way for designing potential therapies for tauopathies C_LI