X11α modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: Mutational analysis of the YENPTY sequence

G. D. King, R. G. Perez, M. L. Steinhilb, J. R. Gaut, R. S. Turner

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

The neuronal adaptor X11α interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Aβ40 and Aβ42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11α-mediated effects on APP trafficking and metabolism, and that X11α modulates APP metabolism in both secretory and endocytic pathways. X11α 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, X11α interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11α with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Aβ40, and Aβ42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11α modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Aβ generated in either pathway.

Original languageEnglish (US)
Pages (from-to)143-154
Number of pages12
JournalNeuroscience
Volume120
Issue number1
DOIs
StatePublished - Aug 4 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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