| First Author | Takeo K | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 29 | Pages | 10544-9 |
| PubMed ID | 25009180 | Mgi Jnum | J:212255 |
| Mgi Id | MGI:5578399 | Doi | 10.1073/pnas.1402171111 |
| Citation | Takeo K, et al. (2014) Allosteric regulation of gamma-secretase activity by a phenylimidazole-type gamma-secretase modulator. Proc Natl Acad Sci U S A 111(29):10544-9 |
| abstractText | gamma-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-beta (Abeta) peptides. Recently, a series of compounds called gamma-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Abeta species (i.e., Abeta42), with a concomitant elevation of the production of shorter Abeta species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of gamma-secretase to augment the proteolytic activity. Analyses using the photoaffinity labeling technique and systematic mutational studies revealed that the phenylimidazole-type GSM targets a previously unidentified extracellular binding pocket within the N-terminal fragment of presenilin (PS). Collectively, we provide a model for the mechanism of action of the phenylimidazole-type GSM in which binding at the luminal side of PS induces a conformational change in the catalytic center of gamma-secretase to modulate Abeta production. |
