title: Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase.
abstract: 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 ofin vitrophosphorylated Tau by activated recombinant ERK2 with nuclear magnetic resonance spectroscopy (NMR) reveals phosphorylation of 15 Ser/Thr sites.In vitrophosphorylation 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.
authors: From Lille University, CNRS UMR8576, F-59000 Lille, France.
authors: Haoling
authors: H
authors: Qi
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Sudhakaran
authors: S
authors: Prabakaran
authors: From Lille University, CNRS UMR8576, F-59000 Lille, France.
authors: François-Xavier
authors: FX
authors: Cantrelle
authors: INSERM UMR1195 Paris SUD University, Le Kremlin Bicêtre 94276, France.
authors: Béatrice
authors: B
authors: Chambraud
authors: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Jeremy
authors: J
authors: Gunawardena
authors: From Lille University, CNRS UMR8576, F-59000 Lille, France.
authors: Guy
authors: http://orcid.org/0000-0002-8236-0901
authors: G
authors: Lippens
authors: From Lille University, CNRS UMR8576, F-59000 Lille, France, isabelle.landrieu@univ-lille1.fr.
authors: Isabelle
authors: I
authors: Landrieu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020816:Amino Acid Motifs; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051381:Rats; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C489131:Mapt protein, rat; D016875:tau Proteins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Alzheimer disease; Tau protein (Tau); extracellular signal-regulated kinase (ERK); nuclear magnetic resonance (NMR); protein phosphorylation; protein-protein interaction