Title: A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis
Authors: Schroeter, Eric H
Ilagan, Ma Xenia G
Brunkan, Anne L
Hecimovic, Silva
Li, Yue-ming
Xu, Min
Lewis, Huw D
Saxena, Meera T
De Strooper, Bart
Coonrod, Archie
Tomita, Taisuke
Iwatsubo, Takeshi
Moore, Chad L
Goate, Alison
Wolfe, Michael S
Shearman, Mark
Kopan, Raphael # ×
Issue Date: Oct-2003
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:100 issue:22 pages:13075-80
Abstract: Notch receptors and the amyloid precursor protein are type I membrane proteins that are proteolytically cleaved within their transmembrane domains by a presenilin (PS)-dependent gamma-secretase activity. In both proteins, two peptide bonds are hydrolyzed: one near the inner leaflet and the other in the middle of the transmembrane domain. Under saturating conditions the substrates compete with each other for proteolysis, but not for binding to PS. At least some Alzheimer's disease-causing PS mutations reside in proteins possessing low catalytic activity. We demonstrate (i) that differentially tagged PS molecules coimmunoprecipitate, and (ii) that PS N-terminal fragment dimers exist by using a photoaffinity probe based on a transition state analog gamma-secretase inhibitor. We propose that gamma-secretase contains a PS dimer in its catalytic core, that binding of substrate is at a site separate from the active site, and that substrate is cleaved at the interface of two PS molecules.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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