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2021-06-17Zeitschriftenartikel DOI: 10.3389/fnmol.2021.661368
Phosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregates
dc.contributor.authorCantrelle, François-Xavier
dc.contributor.authorLoyens, Anne
dc.contributor.authorTrivelli, Xavier
dc.contributor.authorReimann, Oliver
dc.contributor.authorDespres, Clément
dc.contributor.authorGandhi, Neha
dc.contributor.authorHackenberger, Christian
dc.contributor.authorLandrieu, Isabelle
dc.contributor.authorSmet-Nocca, Caroline
dc.date.accessioned2021-09-09T08:42:40Z
dc.date.available2021-09-09T08:42:40Z
dc.date.issued2021-06-17none
dc.date.updated2021-07-01T17:05:22Z
dc.identifier.urihttp://edoc.hu-berlin.de/18452/23973
dc.description.abstractPhosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer’s disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396/pS404) and encompasses S400 as the major O-GlcNAc site of Tau while two additional O-GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O-GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3β alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O-GlcNAcylation of S400. Finally, the role of phosphorylation and O-GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O-GlcNAcylation slows down the rate of fibrillar assembly while GSK3β phosphorylation stimulates aggregation counteracting the effect of glycosylation.eng
dc.language.isoengnone
dc.publisherHumboldt-Universität zu Berlin
dc.rights(CC BY 4.0) Attribution 4.0 Internationalger
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAlzheimer’s diseaseeng
dc.subjectmicrotubule-associated protein taueng
dc.subjectphosphorylationeng
dc.subjectO-GlcNAc glycosylationeng
dc.subjectprotein aggregationeng
dc.subjectNMR spectroscopyeng
dc.subject.ddc610 Medizin und Gesundheitnone
dc.titlePhosphorylation and O-GlcNAcylation of the PHF-1 Epitope of Tau Protein Induce Local Conformational Changes of the C-Terminus and Modulate Tau Self-Assembly Into Fibrillar Aggregatesnone
dc.typearticle
dc.identifier.urnurn:nbn:de:kobv:11-110-18452/23973-0
dc.identifier.doi10.3389/fnmol.2021.661368none
dc.identifier.doihttp://dx.doi.org/10.18452/23326
dc.type.versionpublishedVersionnone
local.edoc.container-titleFrontiers in molecular neurosciencenone
local.edoc.pages18none
local.edoc.type-nameZeitschriftenartikel
local.edoc.institutionMathematisch-Naturwissenschaftliche Fakultätnone
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-publisher-nameFrontiers Research Foundationnone
local.edoc.container-publisher-placeLausannenone
local.edoc.container-volume14none
dc.description.versionPeer Reviewednone
local.edoc.container-articlenumber661368none
dc.identifier.eissn1662-5099

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