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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2021
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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. |
format | Online Article Text |
id | pubmed-8704032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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