Molecular mechanism of intramembrane proteolysis by γ-secretase

• Published in: Journal of biochemistry (Tokyo) 2014-10, Vol.156 (4), p.195-201
• Main Author: Tomita, Taisuke
• Format: Article
• Language: English
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Biocatalysis; Lipid Bilayers - metabolism; Proteolysis
• ISSN: 0021-924X; 1756-2651
• DOI: 10.1093/jb/mvu049

Presenilin is a membrane-embedded intramembrane-cleaving protease with a conserved catalytic G×GD motif. It is the catalytic subunit of γ-secretase, which plays critical roles in developmental biology and the molecular etiology of Alzheimer disease, together with three membrane protein cofactors, nicastrin, Aph-1 and Pen-2. Biochemical and enzymatic analyses have revealed that γ-secretase executes two types of proteolytic activities on a single substrate; an endopeptidase-like cleavage followed by carboxypeptidase-like processive cleavage. Utilizing small molecule inhibitors/modulators together with the substituted cysteine accessibility method, we identified certain residues and regions of presenilin that contribute to the formation of a catalytic pore structure within the lipid bilayer required for its intramembrane-cleaving activity. Recently, determination of the crystal structure of the archaeal presenilin homologue has confirmed the intramembranous location of the two conserved and essential aspartates. In this review, I will introduce the recent progresses in the understanding of the molecular mechanisms of action of this atypical protease.