A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis

Eric H. Schroeter, Ma Xenia G. Ilagan, Anne L. Brunkan, Silva Hecimovic, Yue Ming Li, Min Xu, Huw D. Lewis, Meera T. Saxena, Bart De Strooper, Archie Coonrod, Taisuke Tomita, Takeshi Iwatsubo, Chad L. Moore, Alison Goate, Michael S. Wolfe, Mark Shearman, Raphael Kopan

Research output: Contribution to journalArticlepeer-review

187 Scopus citations

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 γ-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 γ-secretase inhibitor. We propose that γ-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.

Original languageEnglish
Pages (from-to)13075-13080
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number22
DOIs
StatePublished - 28 Oct 2003
Externally publishedYes

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