Dual role of α-secretase cleavage in the regulation of γ-secretase activity for amyloid production Journal Article
| Authors: | Tian, Y.; Crump, C. J.; Li, Y. M. |
| Article Title: | Dual role of α-secretase cleavage in the regulation of γ-secretase activity for amyloid production |
| Abstract: | Processing of the amyloid precursor protein (APP) by β- and γ-secretases generates pathogenic β-amyloid (Aβ) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by α-secretases precludes Aβ formation. Little is known about the role of α-secretase cleavage in γ-secretase regulation. Here, we show that α-secretase-cleaved APP C-terminal product (αCTF) functions as an inhibitor of γ-secretase. We demonstrate that the substrate inhibitory domain (ASID) within αCTF, which is bisected by the α-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns αCTF into a better substrate for γ-secretase. Moreover, α-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of γ-secretase activity by αCTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | controlled study; human cell; protein domain; protein function; proteins; animals; enzyme inhibition; embryo; cell line; membrane proteins; in vitro study; enzyme activity; enzyme substrate; amino acid sequence; molecular sequence data; protein synthesis; peptides; down regulation; feedback system; in-vitro; glycoproteins; alzheimer disease; protein cleavage; inhibitory effect; substrates; adam proteins; amyloid precursor protein secretases; gamma secretase; amyloid; amyloid beta protein; amyloid beta-protein precursor; amyloid precursor proteins; secretases; cellular system; cleavage sites; dual role; feedback mechanisms; inhibitory domains; alpha secretase |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 285 |
| Issue: | 42 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2010-10-15 |
| Start Page: | 32549 |
| End Page: | 32556 |
| Language: | English |
| DOI: | 10.1074/jbc.M110.128439 |
| PUBMED: | 20675367 |
| PROVIDER: | scopus |
| PMCID: | PMC2952257 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 20 April 2011" - "CODEN: JBCHA" - "Source: Scopus" |
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