A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms

[Image: see text] Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule com...

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Autores principales: Brotzakis, Z. Faidon, Lindstedt, Philip R., Taylor, Ross J., Rinauro, Dillon J., Gallagher, Nicholas C. T., Bernardes, Gonçalo J. L., Vendruscolo, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704032/
https://www.ncbi.nlm.nih.gov/pubmed/34963892
http://dx.doi.org/10.1021/acscentsci.1c00585
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author Brotzakis, Z. Faidon
Lindstedt, Philip R.
Taylor, Ross J.
Rinauro, Dillon J.
Gallagher, Nicholas C. T.
Bernardes, Gonçalo J. L.
Vendruscolo, Michele
author_facet Brotzakis, Z. Faidon
Lindstedt, Philip R.
Taylor, Ross J.
Rinauro, Dillon J.
Gallagher, Nicholas C. T.
Bernardes, Gonçalo J. L.
Vendruscolo, Michele
author_sort Brotzakis, Z. Faidon
collection PubMed
description [Image: see text] Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202–395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms.
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spelling pubmed-87040322021-12-27 A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms Brotzakis, Z. Faidon Lindstedt, Philip R. Taylor, Ross J. Rinauro, Dillon J. Gallagher, Nicholas C. T. Bernardes, Gonçalo J. L. Vendruscolo, Michele ACS Cent Sci [Image: see text] Tau is a microtubule-associated protein that regulates the stability of microtubules. We use metainference cryoelectron microscopy, an integrative structural biology approach, to determine an ensemble of conformations representing the structure and dynamics of a tau-microtubule complex comprising the entire microtubule-binding region of tau (residues 202–395). We thus identify the ground state of the complex and a series of excited states of lower populations. A comparison of the interactions in these different states reveals positions along the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilizing effects, which we validate by using site-specific post-translationally modified tau variants obtained by chemical mutagenesis. Taken together, these results illustrate how the simultaneous determination of ground and excited states of macromolecular complexes reveals functional and regulatory mechanisms. American Chemical Society 2021-12-08 2021-12-22 /pmc/articles/PMC8704032/ /pubmed/34963892 http://dx.doi.org/10.1021/acscentsci.1c00585 Text en © 2021 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Brotzakis, Z. Faidon
Lindstedt, Philip R.
Taylor, Ross J.
Rinauro, Dillon J.
Gallagher, Nicholas C. T.
Bernardes, Gonçalo J. L.
Vendruscolo, Michele
A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title_full A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title_fullStr A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title_full_unstemmed A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title_short A Structural Ensemble of a Tau-Microtubule Complex Reveals Regulatory Tau Phosphorylation and Acetylation Mechanisms
title_sort structural ensemble of a tau-microtubule complex reveals regulatory tau phosphorylation and acetylation mechanisms
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704032/
https://www.ncbi.nlm.nih.gov/pubmed/34963892
http://dx.doi.org/10.1021/acscentsci.1c00585
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