S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biochemistry & Molecular Biology (생화학교실) Journal Papers (저널논문_생화학교실)
Rac1 changes the substrate specificity of gamma-secretase between amyloid precursor protein and Notch1
- Boo, Jung Hyun; Sohn, Ji Hoon; Kim, Ji Eun; Song, Hyundong; Mook-Jung, Inhee
- Issue Date
- Biochemical and Biophysical Research Communications 372(4):913-917
- Alzheimer Disease/drug therapy/metabolism; Aminoquinolines/pharmacology; Amyloid Precursor Protein Secretases/*metabolism; Amyloid beta-Protein/metabolism; Amyloid beta-Protein Precursor/*metabolism; Animals; COS Cells; Cell Line; Cercopithecus aethiops; Drug Design; Enzyme Activation; Humans; Presenilin-1/metabolism; Protein Structure, Tertiary; Pyrimidines/pharmacology; Receptor, Notch1/genetics/*metabolism; Sequence Deletion; Substrate Specificity; rac1 GTP-Binding Protein/antagonists & inhibitors/genetics/*metabolism
- Beta amyloid peptide is generated from amyloid precursor protein (APP) by proteolytic cleavage of beta- and gamma-secretases, and plays a critical role in the pathogenesis of Alzheimer's disease. Since gamma-secretase cleaves several proteins including APP and Notch in a number of cell types, it is important to understand the conditions determining gamma-secretase substrate specificity. In the present study, inhibition of Rac1 attenuated gamma-secretase activity for APP, resulting in decreased production of the APP intracellular domain but accumulated C-terminal fragments (APP-CTF). In contrast, Rac1 inhibitor, NSC23766 increased production of the Notch1 intracellular domain but slightly decreased the ectodomain-shed form of Notch1 (NotchDeltaE). To elucidate the mechanism underlying these observations, we performed co-immunoprecipitation experiments to analyze the interaction between Rac1 and presenilin1 (PS1), a component of the gamma-secretase complex. Inhibition of Rac1 enhanced its interaction with PS1. Under the same condition, PS1 interacted more strongly with NotchDeltaE than with APP-CTF. Our results suggested that PS1 determines the preferred substrate for gamma-secretase between APP and Notch1, depending on the activation status of Rac1.
- 1090-2104 (Electronic)
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