Is gamma-secretase a multienzyme complex for membrane protein degradation? Models and speculations

The beta- and gamma-secretases cleave the amyloid protein precursor (APP) to release the amyloid protein (Abeta). While the beta-secretase has now been identified, the gamma-secretase remains an enigma. A number of mutations in the presenilins (PS) and APP have been shown to alter the cleavage specificity of gamma-secretase. However, the relationship between PS and gamma-secretase remains unclear. This article presents some models of gamma-secretase and suggests that the simplest interpretation of current data is that gamma-secretase is a complex of several proteases located in the lumen of secretory vesicles.