1. 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
- Author
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Cantrelle, François-Xavier, Loyens, Anne, Trivelli, Xavier, Reimann, Oliver, Despres, Clément, Gandhi, Neha, Hackenberger, Christian, Landrieu, Isabelle, Smet-Nocca, Caroline, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Biologie Structurale Intégrative (ERL 9002 - BSI ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut Michel Eugène Chevreul - FR 2638 (IMEC), Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Leibniz Forschungsinstitut für Molekulare Pharmakolgie = Leibniz Institute for Molecular Pharmacology [Berlin, Allemagne] (FMP), Leibniz Association, Humboldt University Of Berlin, Queensland University of Technology [Brisbane] (QUT), This work was supported by the Mizutani Foundation for Glycoscience (2018 Research Grant number 180122), the program PHC Procope/DAAD 2015 (project 33334TK) and by grants from the LabEx (Laboratory of Excellence) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease). The NMR facilities were funded by the Council of Région Nord, CNRS, Pasteur Institute of Lille, European Community (FEDER), French Research Ministry and the University of Lille and by the CTRL CPER cofounded by the European Union with the European Regional Development Fund (ERDF), by the Hauts-de-France Regional Council, Métropole Européenne de Lille, and French State. We acknowledge support from the TGE RMN THC (FR-3050, France), Lille NMR and RPE Health and Biology core facility., Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Université d'Artois (UA)-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Centrale Lille Institut (CLIL), Humboldt-Universität zu Berlin, and Landrieu, Isabelle
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phosphorylation ,[SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,macromolecular substances ,protein aggregation ,[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,NMR spectroscopy ,mental disorders ,O-GlcNAc glycosylation ,ddc:610 ,microtubule-associated protein tau ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,610 Medizin und Gesundheit ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Alzheimer’s disease ,Neuroscience ,Original Research - Abstract
International audience; Phosphorylation 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.
- Published
- 2021