A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch1 and APP proteolysis (CROSBI ID 116086)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Schroeter, EH ; Ilagan, MXG ; Brunkan, AL ; Hećimović, Silva ; Li, Y-M ; Xu, M ; Lewis, HD ; Saxena, MT ; De Strooper, B ; Coonrod, A ; Tomita, T ; Iwatsubo, T ; Moore, CL ; Shearman, M ; Goate, A ; Wolfe, MS ; Kopan, R
engleski
A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch1 and APP proteolysis
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.
Alzheimer's disease; Dementia; Gamma-secretase; Neurodegeneration; Presenilin
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Podaci o izdanju
100
2003.
13075-80-x
objavljeno
0027-8424