Complex regulation of γ-secretase: From obligatory to modulatory subunits

Abstract

γ-Secretase is a four subunit, 19-pass transmembrane enzyme that cleaves amyloid precursor protein (APP), catalyzing the formation of amyloid beta (Aß) peptides that form amyloid plaques, which contribute to Alzheimer's disease (AD) pathogenesis. γSecretase also cleaves Notch, among many other type I transmembrane substrates. Despite its seemingly promiscuous enzymatic capacity, γsecretase activity is tightly regulated. This regulation is a function of many cellular entities, including but not limited to the essential γsecretase subunits, nonessential (modulatory) subunits, and γsecretase substrates. Regulation is also accomplished by an array of cellular events, such as presenilin (active subunit of γsecretase) endoproteolysis and hypoxia. In this review we discuss how γsecretase is regulated with the hope that an advanced understanding of these mechanisms will aid in the development of effective therapeutics for γsecretase-associated diseases like AD and Notch-addicted cancer.