In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 29 ( 2014-07-22), p. 10544-10549
Abstract:
γ-Secretase is an intramembrane-cleaving protease responsible for the generation of amyloid-β (Aβ) peptides. Recently, a series of compounds called γ-secretase modulators (GSMs) has been shown to decrease the levels of long toxic Aβ species (i.e., Aβ42), with a concomitant elevation of the production of shorter Aβ species. In this study, we show that a phenylimidazole-type GSM allosterically induces conformational changes in the catalytic site of γ-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 γ-secretase to modulate Aβ production.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1402171111
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2014
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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