期刊
JOURNAL OF BIOCHEMISTRY
卷 156, 期 4, 页码 195-201出版社
OXFORD UNIV PRESS
DOI: 10.1093/jb/mvu049
关键词
Alzheimer disease; amyloid-beta peptide; membrane protein; protease; secretase
资金
- Japan Society for the Promotion of Science
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Science and Technology Corporation
- Core Research for Evolutional Science and Technology of JST, Japan
- Takeda Science Foundation
- Cell Science Research Foundation
Presenilin is a membrane-embedded intramembrane-cleaving protease with a conserved catalytic GxGD motif. It is the catalytic subunit of c-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 c-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.
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