Presenilin 1 Mutations Activate γ42-Secretase but Reciprocally Inhibit ε-Secretase Cleavage of Amyloid Precursor Protein (APP) and S3-Cleavage of Notch

Fusheng Chen, YongJun Gu, Hiroshi Hasegawa, Xueying Ruan, Shigeki Arawaka, Paul Fraser, David Westaway, Howard Mount, Peter St George-Hyslop
2002 Journal of Biological Chemistry  
The presenilin 1 (PS1) and presenilin 2 (PS2) proteins are necessary for proteolytic cleavage of the amyloid precursor protein (APP) within its transmembrane domain. One of these cleavage events (termed ␥-secretase) generates the C-terminal end of the A␤-peptide by proteolysis near residue 710 or 712 of APP 770 . Another event (termed ␥-like or ⑀-secretase cleavage) cleaves near residue 721 at ϳ2-5 residues inside the cytoplasmic membrane boundary to generate a series of stable, C-terminal APP
more » ... le, C-terminal APP fragments. This latter cleavage is analogous to S3-cleavage of Notch. We report here that specific mutations in the N terminus, loop, or C terminus of PS1 all increase the production of A␤ 42 but cause inhibition of both ⑀-secretase cleavage of APP and S3-cleavage of Notch. These data support the hypothesis that ⑀-cleavage of APP and S3-cleavage of Notch are similar events. They also argue that, although both the ␥-site and the ⑀-site cleavage of APP are presenilin-dependent, they are likely to be independent catalytic events.
doi:10.1074/jbc.m205093200 pmid:12119298 fatcat:fcs3vkqpybdpbokn67jmpdb6eq