GSAP modulates γ-secretase specificity by inducing conformational change in PS1.
Proc Natl Acad Sci U S A
; 116(13): 6385-6390, 2019 03 26.
Article
em En
| MEDLINE
| ID: mdl-30850537
ABSTRACT
The mechanism by which γ-secretase activating protein (GSAP) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aß production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active-site-directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of the PS1 N-terminal fragment and the PS1 C-terminal fragment, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.
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MEDLINE
Assunto principal:
Proteínas
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Secretases da Proteína Precursora do Amiloide
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Presenilina-1
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article