X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence.
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.
King
G D
GD
Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA.
Perez
R G
RG
Steinhilb
M L
ML
Gaut
J R
JR
Turner
R S
RS
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins