Important functional role of residue x of the presenilin GxGD protease active site motif for APP substrate cleavage specificity and substrate selectivity of γ-secretase.

γ-Secretase plays a central role in the generation of the Alzheimer disease-causing amyloid β-peptide (Aβ) from the β-amyloid precursor protein (APP) and is thus a major Alzheimer's disease drug target. As several other γ-secretase substrates including Notch1 and CD44 have crucial signaling functions, an understanding of the mechanism of substrate recognition and cleavage is key for the development of APP selective γ-secretase-targeting drugs. The γ-secretase active site domain in its catalytic subunit presenilin (PS) 1 has been implicated in substrate recognition/docking and cleavage.

Requirement for small side chain residues within the GxGD-motif of presenilin for gamma-secretase substrate cleavage.

gamma-Secretase is a pivotal intramembrane-cleaving protease complex and important drug target for Alzheimer's disease. The protease not only releases small peptides, such as the amyloid-beta peptide, which drives Alzheimer's disease pathogenesis, but also intracellular domains, which can have critical functions in nuclear signaling. Unlike typical aspartyl proteases, gamma-secretase contains a non-classical GxGD active site motif in its catalytic subunit presenilin (PS) 1 or PS2.