Article
- The EMBO Journal (2002) 21, 5408 - 5416
- doi:10.1093/emboj/cdf541
Subject Categories:
Presenilins mediate a dual intramembranous 
-secretase cleavage of Notch-1
Masayasu Okochi1, Harald Steiner2, Akio Fukumori1, Hisashi Tanii1, Taisuke Tomita3, Toshihisa Tanaka1, Takeshi Iwatsubo3, Takashi Kudo1, Masatoshi Takeda1 and Christian Haass2
- Department of Post-Genomics and Diseases, Division of Psychiatry and Behavioral Proteomics, Osaka University Graduate School of Medicine, 565-0871 Osaka, Japan
- Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, D-80336 Munich, Germany
- Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 113-0033 Tokyo, Japan
Correspondence to:
Masatoshi Takeda, E-mail: mtakeda@psy.med.osaka-u.ac.jp
Received 2 July 2002; Accepted 21 August 2002; Revised 14 August 2002
Abstract
Following ectodomain shedding, Notch-1 undergoes presenilin (PS)-dependent constitutive intramembranous endoproteolysis at site-3. This cleavage is similar to the PS-dependent 
-secretase cleavage of the 
-amyloid precursor protein (APP). However, topological differences in cleavage resulting in amyloid -peptide (A) or the Notch-1 intracellular domain (NICD) indicated independent mechanisms of proteolytic cleavage. We now demonstrate the secretion of an N-terminal Notch-1 A-like fragment (N). Analysis of N by MALDI-TOF MS revealed that N is cleaved at a novel site (site-4, S4) near the middle of the transmembrane domain. Like the corresponding cleavage of APP at position 40 and 42 of the A 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 APP. Considering these similarities between intramembranous processing of Notch and APP, we conclude that these proteins are cleaved by a common mechanism utilizing the same protease, i.e. PS/-secretase.
Keywords:
- Notch signaling,
- Notch-1- peptide,
- presenilin,
- -secretase,
- site-4 cleavage
