Rac1 changes the substrate specificity of gamma-secretase between amyloid precursor protein and Notch1.
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.
Interdisciplinary Program in Brain Science, School of Biological Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Jung Hyun
JH
Boo
Ji Hoon
JH
Sohn
Ji Eun
JE
Kim
Hyundong
H
Song
Inhee
I
Mook-Jung
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000634:Aminoquinolines / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D053764:Presenilin-1 / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D013379:Substrate Specificity; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000634:Aminoquinolines; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C487513:NSC 23766; D053764:Presenilin-1; D011743:Pyrimidines; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases; D020830:rac1 GTP-Binding Protein