TY - JOUR
T1 - X11α modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein
T2 - Mutational analysis of the YENPTY sequence
AU - King, G. D.
AU - Perez, R. G.
AU - Steinhilb, M. L.
AU - Gaut, J. R.
AU - Turner, R. S.
N1 - Funding Information:
This work was supported by grants from the American Federation for Aging Research, Alzheimer's Association, and US Public Health Service (P50 AG08671), and by the VAMC GRECC. Ms G. King is supported by an NINDS National Research Service Award. We thank Dr. N. Suzuki (Takeda) for antibodies BAN-50, BA-27, and BC-05, Drs. B. Margolis and J.-P. Borg (University of Michigan) for X11α constructs, and S. Skinner, Drs. C. Edwards, M. Gross (University of Michigan) for their assistance.
PY - 2003/8/4
Y1 - 2003/8/4
N2 - 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.
AB - 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.
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U2 - 10.1016/S0306-4522(03)00284-7
DO - 10.1016/S0306-4522(03)00284-7
M3 - Article
C2 - 12849748
AN - SCOPUS:0037827785
VL - 120
SP - 143
EP - 154
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
IS - 1
ER -