Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications.
J Biol Chem
; 278(19): 16470-3, 2003 May 09.
Article
en En
| MEDLINE
| ID: mdl-12644463
ABSTRACT
Gamma-secretase is a protease complex of four integral membrane proteins, with presenilin (PS) as the apparent catalytic component, and this enzyme processes the transmembrane domains of a variety of substrates, including the amyloid beta-protein precursor and the Notch receptor. Here we explore the mechanisms of structurally diverse gamma-secretase inhibitors by examining their ability to displace an active site-directed photoprobe from PS heterodimers. Most gamma-secretase inhibitors, including a potent inhibitor of the PS-like signal peptide peptidase, blocked the photoprobe from binding to PS1, indicating that these compounds either bind directly to the active site or alter it through an allosteric interaction. Conversely, some reported inhibitors failed to displace this interaction, demonstrating that these compounds do not interfere with the protease by affecting its active site. Differential effects of the inhibitors with respect to photoprobe displacement and in cell-based and cell-free assays suggest that these compounds are important mechanistic tools for deciphering the workings of this intramembrane-cleaving protease complex and its similarity to other polytopic aspartyl proteases.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Endopeptidasas
/
Inhibidores Enzimáticos
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2003
Tipo del documento:
Article
País de afiliación:
Estados Unidos