Role of 14-3-3gamma in FE65-dependent gene transactivation mediated by the amyloid beta-protein precursor cytoplasmic fragment.
The amyloid beta-protein precursor intracellular domain fragment (AICD) is generated from amyloid beta-protein precursor by consecutive cleavages. AICD is thought to activate FE65-dependent gene expression, but the molecular mechanism remains under consideration. We found that dimeric 14-3-3gamma bound both AICD and FE65 simultaneously, and this binding facilitated FE65-dependent gene transactivation by enhancing the association of AICD with FE65. 14-3-3gamma bound to the 667VTPEER672 motif of AICD and, most interestingly, the phosphorylation of AICD at Thr-668 in this motif inhibited the interaction with 14-3-3gamma and blocked gene transactivation. 14-3-3gamma required a sequence between the WW domain and the first phosphotyrosine interaction domain of FE65 for association with FE65. Deletion of this region blocked 14-3-3gamma binding to FE65 and suppressed AICD-mediated FE65-dependent gene transactivation, although the deletion mutant FE65 was still able to bind Tip60, a histone acetyltransferase that forms a complex with FE65 in the nucleus. Taken together, these data demonstrate that 14-3-3gamma facilitates FE65-dependent gene transactivation by forming a complex containing AICD and FE65, and phosphorylation of AICD down-regulates FE65-dependent gene transactivation through the dissociation of 14-3-3gamma and/or FE65 from AICD. Our findings suggest that multiple interactions of AICD with FE65 and 14-3-3gamma modulate FE65-dependent gene transactivation.
Sumioka
Akio
A
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
Nagaishi
Shinsuke
S
Yoshida
Tomohiro
T
Lin
Anning
A
Miura
Masayuki
M
Suzuki
Toshiharu
T
D048948:14-3-3 Proteins / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D003593:Cytoplasm / Q000502:physiology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D015533:Transcriptional Activation / Q000502:physiology*
D048948:14-3-3 Proteins; C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5