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Zinc induces temperature-dependent reversible self-assembly of Tau
- Source :
- Journal of Molecular Biology, Journal of Molecular Biology, 2018, ⟨10.1016/j.jmb.2018.12.008⟩, Journal of Molecular Biology, Elsevier, 2018, ⟨10.1016/j.jmb.2018.12.008⟩
- Publication Year :
- 2019
- Publisher :
- Elsevier, 2019.
-
Abstract
- International audience; Tau is an intrinsically disordered microtubule associated protein that is implicated in several neurodegenerative disorders called Tau opathies. 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.
- Subjects :
- Amyloid
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
chemistry.chemical_element
[SDV.CAN]Life Sciences [q-bio]/Cancer
tau Proteins
Zinc
Polymerization
03 medical and health sciences
0302 clinical medicine
Dynamic light scattering
Structural Biology
mental disorders
Humans
Chelation
Binding site
Molecular Biology
030304 developmental biology
Neurons
0303 health sciences
Binding Sites
Heparin
Chemistry
Temperature
Neurodegenerative Diseases
Isothermal titration calorimetry
In vitro
[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics
Biophysics
Turbidimetry
Tau
Protein Processing, Post-Translational
Aggregation self - assembly
030217 neurology & neurosurgery
Intracellular
Subjects
Details
- Language :
- English
- ISSN :
- 00222836 and 10898638
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular Biology, Journal of Molecular Biology, 2018, ⟨10.1016/j.jmb.2018.12.008⟩, Journal of Molecular Biology, Elsevier, 2018, ⟨10.1016/j.jmb.2018.12.008⟩
- Accession number :
- edsair.doi.dedup.....75769f5377c3cb27491cb9c43fb8081b