An APP inhibitory domain containing the Flemish mutation residue modulates gamma-secretase activity for A beta production

作者：Tian Yuan; Bassit Bhramdeo; Chau Deming; Li Yue Ming^*

来源：Nature Structural & Molecular Biology, 2010, 17(2): 151-U3.

DOI：10.1038/nsmb.1743

gamma-secretase is an aspartyl protease that cleaves multiple substrates within their transmembrane domains. gamma-secretase processes the amyloid precursor protein (APP) to generate beta-amyloid (A beta) peptides associated with Alzheimer's disease. Here, we show that APP possesses a substrate inhibitory domain (ASID) that negatively modulates gamma-secretase activity for A beta production by binding to an allosteric site within the gamma-secretase complex. Alteration of this ASID by deletion or mutation, as is seen with the Flemish mutation (A21G), reduces its inhibitory potency and promotes A beta production. Notably, peptides derived from ASID show selective inhibition of gamma-secretase activity for A beta production over Notch1 processing. Therefore, this mode of regulation represents an unprecedented mechanism for modulating gamma-secretase, providing insight into the molecular basis of Alzheimer's disease pathogenesis and a potential strategy for the development of therapeutics.

• 出版日期2010-2