Binding of two zinc ions promotes liquid-liquid phase separation of Tau
Tau is a naturally disordered microtubule associated protein which forms intraneuronal aggregates in several neurodegenerative diseases including Alzheimer's disease (AD). It was reported that zinc interaction with tau protein can trigger its aggregation. Recently we identified three zinc bindi...
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Veröffentlicht in: | International journal of biological macromolecules 2022-12, Vol.223 (Pt A), p.1223-1229 |
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Sprache: | eng |
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Zusammenfassung: | Tau is a naturally disordered microtubule associated protein which forms intraneuronal aggregates in several neurodegenerative diseases including Alzheimer's disease (AD). It was reported that zinc interaction with tau protein can trigger its aggregation. Recently we identified three zinc binding sites located in the N-terminal part, repeat region and the C-terminal part of tau. Here we characterized zinc binding to each of the three sites using isothermal titration calorimetry (ITC) and determined the impact of each site on aggregation using dynamic light scattering (DLS) assays. First, we confirmed the presence of three zinc binding sites on tau and determined the thermodynamic parameters of binding of zinc to these sites. We found a high-affinity zinc binding site located in the repeat region of tau and two N- and C-terminus binding sites with a lower binding constant for zinc. Second, we showed that tau aggregation necessitates zinc binding to the high affinity site in the R2R3 region, while LLPS necessitates zinc binding to any two binding sites. With regard to the role of zinc ions in the aggregation of proteins in neurodegenerative diseases, these findings bring new insights to the understanding of the aggregation mechanism of tau protein induced by zinc.
•Zinc is known to trigger tau aggregation and droplet formation.•Three zinc-binding sites have been identified in a NMR study.•Zinc binding site located in the R2R3 domain is crucial for tau aggregation.•Zinc binding to only one site does not induce tau aggregation nor LLPS.•Any two of three existing zinc-binding sites are necessary to induce droplets. |
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ISSN: | 0141-8130 1879-0003 |
DOI: | 10.1016/j.ijbiomac.2022.11.060 |