A Novel ε-Cleavage within the Transmembrane Domain of the Alzheimer Amyloid Precursor Protein Demonstrates Homology with Notch Processing
- 30 January 2002
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 41 (8), 2825-2835
- https://doi.org/10.1021/bi015794o
Abstract
Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the γ-secretase site. This was termed ε-cleavage. Brefeldin A treatment and pulse−chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of ε-cleavage is decreased by expression of presenilin-1 mutants known to impair Aβ formation, and it is sensitive to the γ-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.Keywords
This publication has 15 references indexed in Scilit:
- The β-Amyloid Precursor Protein Functions as a Cytosolic Anchoring Site That Prevents Fe65 Nuclear TranslocationJournal of Biological Chemistry, 2001
- A Novel γ-Secretase Assay Based on Detection of the Putative C-terminal Fragment-γ of Amyloid β Protein PrecursorPublished by Elsevier ,2001
- Cell‐free assays for γ‐secretase activityThe FASEB Journal, 2000
- The Transmembrane Aspartates in Presenilin 1 and 2 Are Obligatory for γ-Secretase Activity and Amyloid β-Protein GenerationJournal of Biological Chemistry, 2000
- Alternative, Non-secretase Processing of Alzheimer's β-Amyloid Precursor Protein during Apoptosis by Caspase-6 and -8Published by Elsevier ,1999
- Involvement of Caspases in Proteolytic Cleavage of Alzheimer’s Amyloid-β Precursor Protein and Amyloidogenic Aβ Peptide FormationCell, 1999
- Mapping the APP/Presenilin (PS) Binding Domains: The Hydrophilic N-Terminus of PS2 Is Sufficient for Interaction with APP and Can Displace APP/PS1 InteractionNeurobiology of Disease, 1999
- Alzheimer's disease-associated presenilin 1 in neuronal cells: Evidence for localization to the endoplasmic reticulum-Golgi intermediate compartmentJournal of Neuroscience Research, 1997
- β-Amyloid Precursor ProteinJournal of Biological Chemistry, 1996
- Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid β protein precursorNature Genetics, 1993