Premium
X11α impairs γ‐ but not β‐cleavage of amyloid precursor protein
Author(s) -
King Gwendalyn D.,
Cherian Kay,
Turner R. Scott
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02234.x
Subject(s) - amyloid precursor protein secretase , amyloid precursor protein , chemistry , secretion , microbiology and biotechnology , cleavage (geology) , proteolysis , alpha secretase , hek 293 cells , immunoprecipitation , intracellular , biochemistry , enzyme , alzheimer's disease , biology , receptor , gene , medicine , paleontology , disease , fracture (geology)
The phosphotyrosine binding domain of the neuronal protein X11α/mint‐1 binds to the C‐terminus of amyloid precursor protein (APP) and inhibits catabolism to β‐amyloid (Aβ), but the mechanism of this effect is unclear. Coexpression of X11α or its PTB domain with APPswe inhibited secretion of Aβ40 but not APPsβswe, suggesting inhibition of γ‐ but not β‐secretase. To further probe cleavage(s) inhibited by X11α, we coexpressed β‐secretase (BACE‐1) or a component of the γ‐secretase complex (PS‐1Δ9) with APP, APPswe, or C99, with and without X11α, in HEK293 cells. X11α suppressed the PS‐1Δ9‐induced increase in Aβ42 secretion generated from APPswe or C99. However, X11α did not impair BACE‐1‐mediated proteolysis of APP or APPswe to C99. In contrast to impaired γ‐cleavage of APPswe, X11α or its PTB domain did not inhibit γ‐cleavage of NotchΔE to NICD (the Notch intracellular domain). The X11α PDZ–PS.1Δ9 interaction did not affect γ‐cleavage activity. In a cell‐free system, X11α did not inhibit the catabolism of APP C‐terminal fragments. These data suggest that X11α may inhibit Aβ secretion from APP by impairing its trafficking to sites of active γ‐secretase complexes. By specifically targeting substrate instead of enzyme X11α may function as a relatively specific γ‐secretase inhibitor.