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A structural ensemble of a tau-microtubule complex reveals regulatory tau phosphorylation and acetylation mechanisms

2021Artigo científico Acesso aberto
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dc.contributor.authorBrotzakis, Z. Faidon
dc.contributor.authorLindstedt, Philip R.
dc.contributor.authorTaylor, Ross J.
dc.contributor.authorRinauro, Dillon J.
dc.contributor.authorGallagher, Nicholas C. T.
dc.contributor.authorBernardes, Gonçalo J. L.
dc.contributor.authorVendruscolo, Michele
dc.date.accessioned2022-01-07T12:34:12Z
dc.date.available2022-01-07T12:34:12Z
dc.date.issued2021
dc.description© 2021 The Authors. Published by American Chemical Society.pt_PT
dc.description.abstractTau 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.pt_PT
dc.description.sponsorshipZ.F.B. would like to acknowledge the Federation of European Biochemical Societies (FEBS) for financial support through a long-term fellowship. R.J.T. is supported by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/M011194), and G.J.L.B. is a Royal Society University Research Fellow (URF/R/180019).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationACS Cent Sci. 2021 Dec 22;7(12):1986-1995pt_PT
dc.identifier.doi10.1021/acscentsci.1c00585pt_PT
dc.identifier.eissn2374-7951
dc.identifier.urihttp://hdl.handle.net/10451/50736
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACS Publicationspt_PT
dc.relation.publisherversionhttps://pubs.acs.org/journal/acsciipt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.titleA structural ensemble of a tau-microtubule complex reveals regulatory tau phosphorylation and acetylation mechanismspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1995pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage1986pt_PT
oaire.citation.titleACS Central Sciencept_PT
oaire.citation.volume7pt_PT
person.familyNameBernardes
person.givenNameGonçalo
person.identifier.orcid0000-0001-6594-8917
person.identifier.scopus-author-id14046757500
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationd1a48067-77b1-4413-b1c7-602fb18c62c0
relation.isAuthorOfPublication.latestForDiscoveryd1a48067-77b1-4413-b1c7-602fb18c62c0

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