Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation
Article first published online: 8 OCT 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 108, Issue 1, pages 33–43, January 2009
How to Cite
Sadik, G., Tanaka, T., Kato, K., Yamamori, H., Nessa, B. N., Morihara, T. and Takeda, M. (2009), Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation. Journal of Neurochemistry, 108: 33–43. doi: 10.1111/j.1471-4159.2008.05716.x
- Issue published online: 4 DEC 2008
- Article first published online: 8 OCT 2008
- Received May 20, 2008; revised manuscript received September 1, 2008; accepted September 2, 2008.
- 14-3-3 protein;
- Alzheimer disease;
- microtubule-associated protein tau;
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.