Role of 14-3-3γ in FE65-dependent gene transactivation mediated by the amyloid β-protein precursor cytoplasmic fragment

Abstract

The amyloid β-protein precursor intracellular domain fragment (AICD) is generated from amyloid β-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 14-3-3γ bound both AICD and FE65 simultaneously, and this binding facilitated FE65-dependent gene transactivation by enhancing the association of AICD with FE65. 14-3-3γ bound to the 667VTPEER672 motif of AICD and, most interestingly, the phosphorylation of AICD at Thr-668 in this motif inhibited the interaction with 14-3-3γ and blocked gene transactivation. 14-3-3γ required a sequence between the WW domain and the first phosphotyrosine interaction domain of FE65 for association with FE65. Deletion of this region blocked 14-3-3γ 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 14-3-3γ 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 14-3-3γ and/or FE65 from AICD. Our findings suggest that multiple interactions of AICD with FE65 and 14-3-3γ modulate FE65-dependent gene transactivation. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.