X11alpha impairs gamma- but not beta-cleavage of amyloid precursor protein.
The phosphotyrosine binding domain of the neuronal protein X11alpha/mint-1 binds to the C-terminus of amyloid precursor protein (APP) and inhibits catabolism to beta-amyloid (Abeta), but the mechanism of this effect is unclear. Coexpression of X11alpha or its PTB domain with APPswe inhibited secretion of Abeta40 but not APPsbetaswe, suggesting inhibition of gamma- but not beta-secretase. To further probe cleavage(s) inhibited by X11alpha, we coexpressed beta-secretase (BACE-1) or a component of the gamma-secretase complex (PS-1Delta9) with APP, APPswe, or C99, with and without X11alpha, in HEK293 cells. X11alpha suppressed the PS-1Delta9-induced increase in Abeta42 secretion generated from APPswe or C99. However, X11alpha did not impair BACE-1-mediated proteolysis of APP or APPswe to C99. In contrast to impaired gamma-cleavage of APPswe, X11alpha or its PTB domain did not inhibit gamma-cleavage of NotchDeltaE to NICD (the Notch intracellular domain). The X11alpha PDZ-PS.1Delta9 interaction did not affect gamma-cleavage activity. In a cell-free system, X11alpha did not inhibit the catabolism of APP C-terminal fragments. These data suggest that X11alpha may inhibit Abeta secretion from APP by impairing its trafficking to sites of active gamma-secretase complexes. By specifically targeting substrate instead of enzyme X11alpha may function as a relatively specific gamma-secretase inhibitor.
King
Gwendalyn D
GD
Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48105, USA.
Cherian
Kay
K
Turner
R Scott
RS
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007668:Kidney; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000493:pharmacokinetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests / Q000379:methods; D021381:Protein Transport; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D029721:Drosophila Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D013460:Sulfur Isotopes; C569042:TJP1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D062826:Zonula Occludens-1 Protein; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C033652:postsynaptic density proteins; C070350:dlg1 protein, Drosophila; D008715:Methionine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human