title: Molecular mechanism of intramembrane proteolysis by γ-secretase.
abstract: 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.
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055162:Biocatalysis; D008051:Lipid Bilayers / Q000378:metabolism; D059748:Proteolysis
chemical_list: D008051:Lipid Bilayers; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer disease; amyloid-β peptide; membrane protein; protease; secretase