The presenilin C-terminus is required for ER-retention, nicastrin-binding and γ-secretase activity

Abstract

γ-Secretase is an intramembrane cleaving protease involved in Alzheimer's disease. γ-Secretase occurs as & high molecular weight complex composed of presenilin (PS1/2), nicasttrin (NCT), anterior pharynx-defective phenotype 1 and PS enliancer 2. Little is known about the cellular mechanisms of γ-secretase assembly. Here we demonstrate that the cytoplasmic tail of PS1 fulfills several functions required for complex formation, retention of unincorporated PS1 and γ-secretase activity. The very C-terminus interacts with the transmembrane domain of NCT and may penetrate into the membrane. Deletion of the last amino acid is sufficient to completely block γ-secretase assembly and release of PS1 from the endoplasmic reticulum (ER). This suggests that unincorporated PS1 is actively retained within the ER. We identified a hydrophobic stretch of amino acids within the cytoplasmic tail of PS1 distinct from the NCT-binding site, which is required to retain unincorporated PS1 within the ER. Deletion of the retention signal results in the release of PS1 from the ER and the assembly of a nonfunctional γ-secretase complex, suggesting that at least a part of the retention motif may also be reauired for the function of PS1.