Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

Tau is an intrinsically disordered microtubule-associated protein that is implicated in several neurodegenerative disorders called tauopathies. In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the imp...

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Veröffentlicht in:Journal of molecular biology 2019-02, Vol.431 (4), p.687-695
Hauptverfasser: Roman, Andrei Yu, Devred, François, Byrne, Deborah, La Rocca, Romain, Ninkina, Natalia N., Peyrot, Vincent, Tsvetkov, Philipp O.
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container_end_page 695
container_issue 4
container_start_page 687
container_title Journal of molecular biology
container_volume 431
creator Roman, Andrei Yu
Devred, François
Byrne, Deborah
La Rocca, Romain
Ninkina, Natalia N.
Peyrot, Vincent
Tsvetkov, Philipp O.
description Tau is an intrinsically disordered microtubule-associated protein that is implicated in several neurodegenerative disorders called tauopathies. In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the importance of this irreversible PHF formation in neurodegenerative disease, Tau aggregation has been extensively studied. Several different factors, such as mutations or post translational modifications, have been shown to influence the formation of late-stage non-reversible Tau aggregates. It was recently shown that zinc ions accelerated heparin-induced oligomerization of Tau constructs. Indeed, in vitro studies of PHFs have usually been performed in the presence of additional co-factors, such as heparin, in order to accelerate their formation. Using turbidimetry, we investigated the impact of zinc ions on Tau in the absence of heparin and found that zinc is able to induce a temperature-dependent reversible oligomerization of Tau. The obtained oligomers were not amyloid-like and dissociated instantly following zinc chelation or a temperature decrease. Finally, a combination of isothermal titration calorimetry and dynamic light scattering experiments showed zinc binding to a high-affinity binding site and three low-affinity sites on Tau, accompanied by a change in Tau folding. Altogether, our findings stress the importance of zinc in Tau oligomerization. This newly identified Zn-induced oligomerization mechanism may be a part of a pathway different of and concurrent to Tau aggregation cascade leading to PHF formation. [Display omitted] •Tau aggregation mechanism is still poorly understood.•Zinc ions induce fast and reversible oligomerization of Tau without heparin.•Tau has 2 types of zinc-binding sites.•Zinc ions binding to tau induces structural changes of tau.•New oligomerization mechanism might be concurrent to PHF formation.
doi_str_mv 10.1016/j.jmb.2018.12.008
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In these diseases, Tau is found in the form of intracellular inclusions that consist of aggregated paired helical filaments (PHFs) in neurons. Given the importance of this irreversible PHF formation in neurodegenerative disease, Tau aggregation has been extensively studied. Several different factors, such as mutations or post translational modifications, have been shown to influence the formation of late-stage non-reversible Tau aggregates. It was recently shown that zinc ions accelerated heparin-induced oligomerization of Tau constructs. Indeed, in vitro studies of PHFs have usually been performed in the presence of additional co-factors, such as heparin, in order to accelerate their formation. Using turbidimetry, we investigated the impact of zinc ions on Tau in the absence of heparin and found that zinc is able to induce a temperature-dependent reversible oligomerization of Tau. The obtained oligomers were not amyloid-like and dissociated instantly following zinc chelation or a temperature decrease. Finally, a combination of isothermal titration calorimetry and dynamic light scattering experiments showed zinc binding to a high-affinity binding site and three low-affinity sites on Tau, accompanied by a change in Tau folding. Altogether, our findings stress the importance of zinc in Tau oligomerization. This newly identified Zn-induced oligomerization mechanism may be a part of a pathway different of and concurrent to Tau aggregation cascade leading to PHF formation. [Display omitted] •Tau aggregation mechanism is still poorly understood.•Zinc ions induce fast and reversible oligomerization of Tau without heparin.•Tau has 2 types of zinc-binding sites.•Zinc ions binding to tau induces structural changes of tau.•New oligomerization mechanism might be concurrent to PHF formation.</description><identifier>ISSN: 0022-2836</identifier><identifier>EISSN: 1089-8638</identifier><identifier>DOI: 10.1016/j.jmb.2018.12.008</identifier><identifier>PMID: 30580037</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>aggregation self-assembly ; Amyloid - metabolism ; Binding Sites - drug effects ; Biochemistry, Molecular Biology ; Biophysics ; Cancer ; Heparin - metabolism ; Humans ; Life Sciences ; Neurobiology ; Neurodegenerative Diseases - metabolism ; Neurons - drug effects ; Neurons - metabolism ; Neurons and Cognition ; Polymerization - drug effects ; Protein Processing, Post-Translational - drug effects ; Tau ; tau Proteins - metabolism ; Temperature ; zinc ; Zinc - pharmacology</subject><ispartof>Journal of molecular biology, 2019-02, Vol.431 (4), p.687-695</ispartof><rights>2018</rights><rights>Copyright © 2018. 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subjects aggregation self-assembly
Amyloid - metabolism
Binding Sites - drug effects
Biochemistry, Molecular Biology
Biophysics
Cancer
Heparin - metabolism
Humans
Life Sciences
Neurobiology
Neurodegenerative Diseases - metabolism
Neurons - drug effects
Neurons - metabolism
Neurons and Cognition
Polymerization - drug effects
Protein Processing, Post-Translational - drug effects
Tau
tau Proteins - metabolism
Temperature
zinc
Zinc - pharmacology
title Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau
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