Presenilin 1 mutations activate gamma 42-secretase but reciprocally inhibit epsilon-secretase cleavage of amyloid precursor protein (APP) and S3-cleavage of notch

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 gamma-secretase) generates the C-terminal end of the Abeta-peptide by proteolysis near residue 71...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2002-09, Vol.277 (39), p.36521-36526
Main Authors: Chen, Fusheng, Gu, YongJun, Hasegawa, Hiroshi, Ruan, Xueying, Arawaka, Shigeki, Fraser, Paul, Westaway, David, Mount, Howard, St George-Hyslop, Peter
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Blotting, Western
Catalysis
Cell Line
Endopeptidases - metabolism
Enzyme Activation
Humans
Mass Spectrometry
Membrane Proteins - genetics
Membrane Proteins - metabolism
Microsomes - metabolism
Models, Genetic
Molecular Sequence Data
Mutation
Precipitin Tests
Presenilin-1
Protein Binding
Protein Structure, Tertiary
Receptors, Notch
Temperature
Transfection
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 gamma-secretase) generates the C-terminal end of the Abeta-peptide by proteolysis near residue 710 or 712 of APP(770). Another event (termed gamma-like or epsilon-secretase cleavage) cleaves near residue 721 at approximately 2-5 residues inside the cytoplasmic membrane boundary to generate a series of stable, 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 Abeta(42) but cause inhibition of both epsilon-secretase cleavage of APP and S3-cleavage of Notch. These data support the hypothesis that epsilon-cleavage of APP and S3-cleavage of Notch are similar events. They also argue that, although both the gamma-site and the epsilon-site cleavage of APP are presenilin-dependent, they are likely to be independent catalytic events.
ISSN:0021-9258