Modulation of amyloid precursor protein metabolism by X11α/Mint-1 -: A deletion analysis of protein-protein interaction domains

Modulation of amyloid precursor protein (APP) metabolism plays a pivotal role in the pathogenesis of Alzheimer's disease. The phosphotyrosine-binding/protein interaction (PTB/PI) domain of X11 alpha, a neuronal cytosolic adaptor protein, binds to the YENPTY sequence in the cytoplasmic carboxyl terminus of APP. This interaction prolongs the half-life of APP and inhibits A beta 40 and A beta 42 secretion. X11 alpha /Mint-1 has multiple protein-protein interaction domains, a (M) under bar unc-18 (int) under bar eraction domain (MID), a Cask/Lin-2 interaction domain (CID), a PTB/PI domain, and two PDZ domains. These X11 alpha protein interaction domains may modulate its effect on APP processing. To test this hypothesis, we performed a deletion analysis of X11 alpha: effects on metabolism of APP,,, Swedish (K595N/M596L) (APP,) by transient cotransfection of HEK 293 cells with: 1) X11 alpha (X11 alpha -wt, N-MID-CID-PTB-PDZ-PDZ-C), 2) amino-terminal deletion (X11 alpha-DeltaN, PTB-PDZ-PDZ), 3) carboxyl-terminal deletion (X11 alpha-Delta PDZ, MID-CID-PTB), or 4) deletion of both termini (PTB domain only, PTB), The carboxyl terminus of X11 alpha was required for stabilization of APP, in cells. In contrast, the amino terminus of X11 alpha was required to stimulate APPs secretion. X11 alpha, X11 alpha-DeltaN, and X11 alpha -PTB, but not X11 alpha-Delta PDZ, were effective inhibitors of A beta 40 and A beta 42 secretion. These results suggest that additional protein interaction domains of X11 alpha modulate various aspects of APP metabolism.