Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1

Presenilin-1 (PS-l) is the most causative Alzheimer gene product, and its function is not well understood. In an attempt to elucidate the function of PS-l, we screened a human brain cDNA library for PS-l-interacting proteins using the yeast two-hybrid system and isolated a novel protein containing a PSD-95/Dlg/ZO-1 (PDZ)-like domain. This novel PS l-associated protein (PSAP) shares a significant similarity with a Caenorhabditis elegans protein of unknown function. Northern blot analysis revealed that PSAP is predominantly expressed in the brain. Deletion of the first four C-terminal amino acid residues of PS-l, which contain the PDZ domain-binding motif (Gln-Phe-Tyr-Ile), reduced the binding activity of PS-l toward PSAP 4-fold. These data suggest that PS-l may associate with a PDZ-Iike domain-containing protein in vivo and thus may participate in receptor or channel clustering and intracellular signaling events in the brain.