Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

• Published in: Journal of molecular biology Vol. 431; no. 4; pp. 687 - 695
• Main Authors: Roman, Andrei Yu, Devred, François, Byrne, Deborah, La Rocca, Romain, Ninkina, Natalia N., Peyrot, Vincent, Tsvetkov, Philipp O.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-02-2019; Elsevier
• 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; ThT; AD; PD; ND; MT; aggregation self-assembly; ITC; Tau; DLS; zinc; PHF; Aggregation self - assembly; Zinc
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2018.12.008

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.
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•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.