期刊
BIOCHEMISTRY
卷 52, 期 1, 页码 61-69出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi301252r
关键词
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资金
- Japan Society for the Promotion of Science (JSPS)
- Japan Science and Technology Corp. (JST)
- Core Research for Evolutional Science and Technology of JST
- Grants-in-Aid for Scientific Research [12J00097, 24659028, 24111511] Funding Source: KAKEN
Presenilin 1 (PS1) comprises a catalytic subunit of gamma-secretase, which is an intramembrane-cleaving protease responsible for generation of amyloid-beta peptides as well as Notch cleavage, the latter being implicated in cancer. We have shown that transmembrane domains (TMDs) 1, 6, 7, and 9 of PSI form the catalytic pore structure within the membrane for intramembrane proteolysis. Here we report a novel monoclonal antibody 9D11, which directly recognizes the TMD1-proximal residues in the hydrophilic loop region. Intriguingly, 9D11 inhibited the gamma-secretase activity irrespective of the binding of known gamma-secretase inhibitors and abolished Notch signaling-dependent cancer cell viability. Our data suggest that the juxtamembrane region of TMD1 of PSI is a novel molecular target for the mechanism-based inhibition of gamma-secretase and the development of the anticancer drug.
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