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PMID: 12374741 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1.

The EMBO journal ·Vol. 21 ·No. 20 ·2002-10-15 ·Pages 5408-16

Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C

Abstract

Following ectodomain shedding, Notch-1 undergoes presenilin (PS)-dependent constitutive intramembranous endoproteolysis at site-3. This cleavage is similar to the PS-dependent gamma-secretase cleavage of the beta-amyloid precursor protein (betaAPP). However, topological differences in cleavage resulting in amyloid beta-peptide (Abeta) or the Notch-1 intracellular domain (NICD) indicated independent mechanisms of proteolytic cleavage. We now demonstrate the secretion of an N-terminal Notch-1 Abeta-like fragment (Nbeta). Analysis of Nbeta by MALDI-TOF MS revealed that Nbeta is cleaved at a novel site (site-4, S4) near the middle of the transmembrane domain. Like the corresponding cleavage of betaAPP at position 40 and 42 of the Abeta domain, S4 cleavage is PS dependent. The precision of this cleavage is affected by familial Alzheimer's disease-associated PS1 mutations similar to the pathological endoproteolysis of betaAPP. Considering these similarities between intramembranous processing of Notch and betaAPP, we conclude that these proteins are cleaved by a common mechanism utilizing the same protease, i.e. PS/gamma-secretase.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amino Acid Sequence Amyloid Precursor Protein Secretases Amyloid beta-Peptides/chemistry,genetics,metabolism Animals Aspartic Acid Endopeptidases Binding Sites Cell Line Cell Membrane/metabolism Endopeptidases/metabolism Humans In Vitro Techniques Membrane Proteins/chemistry,genetics,metabolism Mice Molecular Sequence Data Mutation Peptide Fragments/chemistry,genetics,metabolism Presenilin-1 Receptor, Notch1 Receptors, Cell Surface Sequence Homology, Amino Acid Transcription Factors
Chemicals
Amyloid beta-Peptides Membrane Proteins NOTCH1 protein, human Notch1 protein, mouse PSEN1 protein, human Peptide Fragments Presenilin-1 Receptor, Notch1 Receptors, Cell Surface Transcription Factors Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Okochi Masayasu
Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan.
Steiner Harald
Fukumori Akio
Tanii Hisashi
Tomita Taisuke
Tanaka Toshihisa
Iwatsubo Takeshi
Kudo Takashi
Takeda Masatoshi
Haass Christian
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdf541
Published
2002-10-15
Pages
5408-16
Language
English
Region
England
NLM ID
8208664
PMCID
PMC129073
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/cdf541 PMC Full Text View journal details
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