X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence.

Academic Article

Abstract

  • The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. However, endocytic-competent APPswe Y743A had unique trafficking and metabolism including a prolonged half-life and increased secretion of catabolites compared with APPswe. In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.
  • Published In

  • Neuroscience  Journal
  • Keywords

  • Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amyloid beta-Protein Precursor, Carrier Proteins, Cell Line, Endocytosis, Humans, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Protein Transport, Sequence Homology, Amino Acid
  • Author List

  • King GD; Perez RG; Steinhilb ML; Gaut JR; Turner RS
  • Start Page

  • 143
  • End Page

  • 154
  • Volume

  • 120
  • Issue

  • 1