Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation

J Neurochem. 2009 Jan;108(1):33-43. doi: 10.1111/j.1471-4159.2008.05716.x. Epub 2008 Nov 10.


The microtubule associated protein tau is a major component of neurofibrillary tangles in Alzheimer disease brain, however the neuropathological processes behind the formation of neurofibrillary tangles are still unclear. Previously, 14-3-3 proteins were reported to bind with tau. 14-3-3 Proteins usually bind their targets through specific serine/threonine -phosphorylated motifs. Therefore, the interaction of tau with 14-3-3 mediated by phosphorylation was investigated. In this study, we show that the phosphorylation of tau by either protein kinase A (PKA) or protein kinase B (PKB) enhances the binding of tau with 14-3-3 in vitro. The affinity between tau and 14-3-3 is increased 12- to 14-fold by phosphorylation as determined by real time surface plasmon resonance studies. Mutational analyses revealed that Ser214 is critical for the phosphorylation-mediated interaction of tau with 14-3-3. Finally, in vitro aggregation assays demonstrated that phosphorylation by PKA/PKB inhibits the formation of aggregates/filaments of tau induced by 14-3-3. As the phosphorylation at Ser214 is up-regulated in fetal brain, tau's interaction with 14-3-3 may have a significant role in the organization of the microtubule cytoskeleton in development. Also as the phosphorylation at Ser214 is up-regulated in Alzheimer's disease brain, tau's interaction with 14-3-3 might be involved in the pathology of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / immunology
  • 14-3-3 Proteins / metabolism*
  • Animals
  • Antibodies / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Immunoprecipitation / methods
  • Phosphorylation* / drug effects
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Serine / metabolism*
  • Surface Plasmon Resonance / methods
  • Time Factors
  • tau Proteins / metabolism*
  • tau Proteins / pharmacology


  • 14-3-3 Proteins
  • Antibodies
  • tau Proteins
  • Serine
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3