The γ-secretase protease complexes in neurodegeneration, cancer and immunity

Abstract

The intramembrane-cleaving proteases (I-CliPs) are necessary for the proteolytic cleavage of several transmembrane proteins and initiation of divergent signalling events. The tetrameric c-secretase protease complexes, comprised of presenilin and three other subunits, represent a major subclass of the I-CliPs. The c-secretase protease complexes are involved in regulated intramembrane proteolysis, an evolutionary conserved and important signal transduction process encompassing the sequential proteolysis of transmembrane substrates that are central to many physiological processes, including embryonic development, haematopoiesis, and normal functioning of the nervous and immune systems. Deregulated intramembrane proteolysis of certain substrates is proposed to be associated with neurodegeneration, cancer and impaired immune function. In this chapter, we summarise the major biochemical and functional properties (structure, catalytic mechanisms, substrate specificities, and regulation) of the c-secretase protease complexes. We also present evidence for a role of γ-secretase protease complexes in neurodegeneration, cancer and inflammatory disease and consider the use of γ-secretase inhibitors as prospective therapeutics in several diseases.