Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and β-catenin

Missense substitutions in the presenilin 1 (PSI) and presenilin 2 (PS2) proteins are associated with early-onset familiar Alzheimer's disease. We have used yeast two-hybrid and coimmunoprecipitation methods to show that the large cytoplasmic loop domains of PSI and PS2 interact specifically with three members of the armadillo protein family, including beta-catenin, p0071, and a novel neuronal-specific armadillo protein-neural plakophilin-related armadillo protein (NPRAP). The PSI:NPRAP interaction occurs between the arm repeats of NPRAP and residues 372-399 at the C-terminal end of the large cytoplasmic loop of PSI. The latter residues contain a single arm-like domain and are highly conserved in the presenilins, suggesting that they form a functional armadillo protein binding site for the presenilins.