An X11[alpha]/FSBP complex represses transcription of the GSK3[beta] gene promoter.

Abstract

X11? is a neuronal adaptor protein that interacts with the amyloid precursor protein (APP) via a centrally located phosphotyrosine binding (PTB) domain to inhibit production of A? peptide that is deposited in Alzheimer's disease brains. X11? also contains two C-terminal postsynaptic density-95, discs large, zona occludens 1 (PDZ) domains and we show here that via its PDZ domains, X11? interacts with a novel transcription factor, fibrinogen silencer binding protein (FSBP). Moreover, we demonstrate that an X11?/FSBP complex signals to the nucleus to repress glycogen synthase kinase-3? (GSK3?) promoter activity. GSK3? is a favoured candidate kinase for phosphorylating tau in Alzheimer's disease. Our findings reveal a new function for X11? that may impact on Alzheimer's disease pathogenesis.