Presenilin-1 Interacts with Plakoglobin and Enhances Plakoglobin-Tcf-4 Association

Alzheimer disease-linked Presenilin-1 (PS1) is a negative modulator of β-catenin/Tcf-4 activity. However, the mechanism underlying this effect is not well understood. We show here that the effects of PS1 on the activity of this complex in epithelial cells are independent of its γ-secretase activity and its interaction with β-catenin. As presented in this report PS1 also binds plakoglobin with similar affinity as β-catenin, although this interaction does not involve equivalent residues in the two catenins. Moreover, PS1 association with plakoglobin enhances the interaction of this molecule with Tcf-4 and prevents its binding to DNA. These effects were observed with the unprocessed form of PS1, which has higher affinity for plakoglobin and β-catenin than processed PS1. These results provide a new explanation for the effects of PS1 on gene transcription mediated by β-catenin in epithelial cells.