An APP inhibitory domain containing the Flemish mutation residue modulates γ-secretase activity for AΒ production Journal Article
| Authors: | Tian, Y.; Bassit, B.; Chau, D.; Li, Y. M. |
| Article Title: | An APP inhibitory domain containing the Flemish mutation residue modulates γ-secretase activity for AΒ production |
| Abstract: | γ-secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. γ-secretase processes the amyloid precursor protein (APP) to generate γ-amyloid (Aγ) peptides associated with Alzheimer's disease. Here, we show that APP possesses a substrate inhibitory domain (ASID) that negatively modulates γ-secretase activity for Aγ production by binding to an allosteric site within the γ-secretase complex. Alteration of this ASID by deletion or mutation, as is seen with the Flemish mutation (A21G), reduces its inhibitory potency and promotes Aγ production. Notably, peptides derived from ASID show selective inhibition of γ-secretase activity for Aγ production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating γ-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | human cell; mutation; mutation, missense; enzyme inhibition; models, biological; protein binding; enzyme activity; hela cell; amino acid sequence; molecular sequence data; cell strain hek293; human cell culture; enzyme inhibitors; substrate specificity; binding site; inhibition kinetics; alzheimer disease; amyloid precursor protein; notch1 receptor; amyloid precursor protein secretases; gamma secretase; allosteric regulation; allosterism; amyloid beta protein; amyloid beta-protein precursor |
| Journal Title: | Nature Structural and Molecular Biology |
| Volume: | 17 |
| Issue: | 2 |
| ISSN: | 1545-9993 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-02-01 |
| Start Page: | 151 |
| End Page: | 158 |
| Language: | English |
| DOI: | 10.1038/nsmb.1743 |
| PUBMED: | 20062056 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: NSMBC" - "Source: Scopus" |
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