Binding of two zinc ions promotes liquid-liquid phase separation of Tau.

Autor: Yatoui D; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Tsvetkov PO; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France. Electronic address: philipp.tsvetkov@univ-amu.fr., La Rocca R; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Baksheeva VE; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Allegro D; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Breuzard G; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Ferracci G; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France., Byrne D; Institut de Microbiologie de la Méditerranée, CNRS, FR3479, Aix-Marseille Université, 13402 Marseille, France., Devred F; Aix Marseille Univ, CNRS, INP, Institute of Neurophysiopathol, Faculté des Sciences Médicales et Paramédicales, Marseille, France. Electronic address: francois.devred@univ-amu.fr.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2022 Dec 31; Vol. 223 (Pt A), pp. 1223-1229. Date of Electronic Publication: 2022 Nov 12.
DOI: 10.1016/j.ijbiomac.2022.11.060
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: