X11 interaction with beta-amyloid precursor protein modulates its cellular stabilization and reduces amyloid beta-protein secretion.
The protein interaction domain of the neuronal protein X11 binds to the YENPTY motif within the cytoplasmic domain of beta-amyloid precursor protein (betaAPP). Amyloid-beta protein (Abeta), the major constituent of the amyloid deposited in brain of Alzheimer's disease patients, is generated by proteolytic processing of betaAPP, which occurs in part following betaAPP internalization. Because the YENPTY motif has a role in the internalization of betaAPP, the effect of X11 binding on betaAPP processing was studied in mouse neuroblastoma N2a, human embryonic kidney 293, monkey kidney COS-1, and human glial U251 cell lines transfected with wild type or mutated betaAPP cDNAs. Secretion of soluble betaAPP via alpha-secretase activity increased significantly in cells transfected with betaAPP variants containing mutations that impair interaction with X11 when compared with cells transfected with wild type cDNA. Cotransfection of betaAPP and X11 caused retention of cellular betaAPP, decreased secretion of sbetaAPPalpha, and decreased Abeta secretion. Thus, betaAPP interaction with the protein interaction domain of X11 stabilizes cellular betaAPP and thereby participates in the regulation of betaAPP processing pathways.
Departments of Pharmacology and Pathology, New York University Medical Center, New York, New York 10016, USA.
M
M
Sastre
R S
RS
Turner
E
E
Levy
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D018076:DNA, Complementary; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding; D014162:Transfection; D014407:Tumor Cells, Cultured
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C513072:Apba1 protein, mouse; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins