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Article Dans Une Revue Journal of Biological Chemistry Année : 2016

Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase

Résumé

Tau neuronal protein has a central role in neurodegeneration and is implicated in Alzheimer disease development. Abnormal phosphorylation of Tau impairs its interaction with other proteins and is associated with its dysregulation in pathological conditions. Molecular mechanisms leading to hyperphosphorylation of Tau in pathological conditions are unknown. Here, we characterize phosphorylation of Tau by extracellular-regulated kinase (ERK2), a mitogen-activated kinase (MAPK) that responds to extracellular signals. Analysis of in vitro phosphorylated Tau by activated recombinant ERK2 with nuclear magnetic resonance spectroscopy (NMR) reveals phosphorylation of 15 Ser/Thr sites. In vitro phosphorylation of Tau using rat brain extract and subsequent NMR analysis identifies the same sites. Phosphorylation with rat brain extract is known to transform Tau into an Alzheimer disease-like state. Our results indicate that phosphorylation of Tau by ERK2 alone is sufficient to produce the same characteristics. We further investigate the mechanism of ERK2 phosphorylation of Tau. Kinases are known to recognize their protein substrates not only by their specificity for a targeted Ser or Thr phosphorylation site but also by binding to linear-peptide motifs called docking sites. We identify two main ERK2 docking sites in Tau sequence using NMR. Our results suggest that ERK2 dysregulation in Alzheimer disease could lead to abnormal phosphorylation of Tau resulting in the pathology of the disease.
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hal-01389831 , version 1 (27-05-2019)

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Haoling Qi, Sudhakaran Prabakaran, François-Xavier Cantrelle, Béatrice Chambraud, Jeremy Gunawardena, et al.. Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase. Journal of Biological Chemistry, 2016, 291 (14), pp.7742 - 7753. ⟨10.1074/jbc.M115.700914⟩. ⟨hal-01389831⟩
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