X11alpha impairs gamma- but not beta-cleavage of amyloid precursor protein.

Academic Article

Abstract

  • 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.
  • Published In

    Keywords

  • Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Aspartic Acid Endopeptidases, Carrier Proteins, Cell Line, Cell-Free System, Drosophila, Drosophila Proteins, Embryo, Mammalian, Embryo, Nonmammalian, Endopeptidases, Enzyme-Linked Immunosorbent Assay, Humans, Immunoblotting, Kidney, Membrane Proteins, Methionine, Nerve Tissue Proteins, Peptide Fragments, Phosphoproteins, Precipitin Tests, Protein Transport, Receptor, Notch1, Receptors, Cell Surface, Sequence Deletion, Sulfur Isotopes, Time Factors, Transcription Factors, Transfection, Tumor Suppressor Proteins, Zonula Occludens-1 Protein
  • Author List

  • King GD; Cherian K; Turner RS
  • Start Page

  • 971
  • End Page

  • 982
  • Volume

  • 88
  • Issue

  • 4