Disease-related Modifications in Tau Affect the Interaction between Fyn and Tau

• Published in: The Journal of biological chemistry 2005-10, Vol.280 (42), p.35119-35125
• Main Authors: Bhaskar, Kiran, Yen, Shu-Hui, Lee, Gloria
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Alzheimer Disease - metabolism; Amino Acid Motifs; Animals; Exons; Genes, Dominant; Glutathione Transferase - metabolism; Humans; Immunohistochemistry; Kinetics; Mice; Mice, Transgenic; Microtubules - metabolism; Models, Genetic; Mutation; Mutation, Missense; Neurodegenerative Diseases - pathology; Phosphorylation; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-fyn - metabolism; Proto-Oncogene Proteins c-fyn - physiology; Recombinant Proteins - chemistry; src Homology Domains; Surface Plasmon Resonance; tau Proteins - genetics; tau Proteins - metabolism; tau Proteins - physiology; Time Factors; Tyrosine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M505895200

Microtubule-associated protein tau is the major component of the neurofibrillary tangles of Alzheimer disease (AD) and is genetically linked to frontotemporal dementias (FTDP-17). We have recently shown that tau interacts with the SH3 domain of Fyn, an Src family non-receptor tyrosine kinase, and is tyrosine-phosphorylated by Fyn on Tyr-18. Also, tyrosine-phosphorylated tau is present in the neuropathology of AD. To determine whether alterations in the tau-Fyn interaction might correlate with disease-related factors in AD and FTDP-17, we have performed real-time surface plasmon resonance studies on a panel of 21 tau constructs with Fyn SH3. We report that the interaction between Fyn SH3 and 3R-tau was 20-fold higher than that with 4R-tau. In addition, the affinity between 4R-tau and Fyn SH3 was increased 25–45-fold by phosphorylation-mimicking mutations or by FTDP-17 mutations. In vitro kinase reactions show that tau, with lower affinity SH3 interactions, exhibited a lower level of Tyr-18 phosphorylation under our reaction conditions. Lastly, we have demonstrated that tau is phosphorylated on Tyr-18 in the tau P301L mouse model for tauopathy (JNPL3). In summary, our results suggest that disease-related phosphorylation and missense mutations of tau increase association of tau with Fyn. Because these effects are mediated through the 4R component of the tau population, these results also have implications for the FTDP-17 diseases caused by increased expression of 4R-tau. Our data support a role for the Fyn-tau interaction in neurodegeneration.