Structure-activity relationship of presenilin in γ-secretase-mediated intramembrane cleavage

Genetic research on familial cases of Alzheimer disease have identified presenilin (PS) as an important membrane protein in the pathomechanism of this disease. PS is the catalytic subunit of gamma-secretase, which is responsible for the generation of amyloid-beta peptide deposited in the brains of Alzheimer disease patients. gamma-Secretase is an atypical protease composed of four membrane proteins (i.e., presenilin, nicastrin, anterior pharynx defective-1 (Aph-1), and presenilin enhancer-2 (Pen-2)) and mediates intramembrane proteolysis. Numerous investigations have been conducted toward understanding the structural features of gamma-secretase components as well as the cleavage mechanism of gamma-secretase. In this review, we summarize our current understanding of the structure and activity relationship of the gamma-secretase complex.