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Structure-function relationship of γ-secretase


Genetic and biological studies provide strong evidence that the production and deposition of amyloid-β peptides (Aβ) contribute to the etiology of Alzheimer’s disease (AD). γ-Secretase is an unusual aspartic protease that cleaves the scissile bond within the transmembrane domain of APP to generate Aβ. This unusual enzyme is composed of a high molecular weight membrane protein complex containing presenilin, nicastrin, Aph-1 and Pen-2. Drugs that regulate the production of Aβ by inhibiting or modulating the γ-secretase activity could provide a disease-modifying effect on AD, although recent studies suggest that the γ-secretase plays important roles in cellular signaling including Notch pathway. Thus, understanding the molecular mechanism whereby the γ-secretase cleaves its substrate is a critical issue for the development of compounds that specifically regulate the Aβ-generating γ-secretase activity.


To analyze the structure of PS, the catalytic subunit of γ-secretase, we have employed substituted cysteine accessibility method (SCAM), a biochemical method by which structures of various membrane proteins have been analyzed in a functional state. In addition, we identified the target molecule/domain of the γ-secretase inhibitors and modulators using chemical biology approach. Finally, we rationally developed novel reagents that regulate the γ-secretase activity.


We found that the hydrophilic “catalytic pore” structure of γ-secretase is formed by the transmembrane domains (TMD) 1, 6, 7 and 9 of PS1 within the membrane. Competition experiments by γ-secretase inhibitors suggest that the N-terminal region of TMD1 directly faces the hydrophilic environment within the lipid bilayer as a part of the catalytic site. Intriguingly, inhibitor binding affected water accessibility of residues at the membrane border of TMD1. Moreover, we successfully raised a novel inhibitory monoclonal antibody against γ-secretase activity, which targets the juxtamembrane region of TMD1 of PS1. Finally, we identified that GSM-1, a potent γ-secretase modulator, binds to the hydrophobic region of TMD1 and affects the catalytic pore structure.


TMD1 of PS1 is a functionally critical domain for the γ-secretase activity.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Tomita, T. Structure-function relationship of γ-secretase. Mol Neurodegeneration 7 (Suppl 1), L5 (2012).

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