Dab1 binds to Fe65 and diminishes the effect of Fe65 or LRP1 on APP processing.
Fe65 and Dab1 are adaptor proteins that interact with the cytoplasmic domain of amyloid precursor protein (APP) via phosphotyrosine-binding (PTB) domain and that affect APP processing and Aβ production. Co-expression of Dab1 with Fe65 and APP resumed nuclear translocation of Fe65 despite of its cytoplasmic anchor, APP. The decreased amount of Fe65 bound to APP was shown in co-immunoprecipitation assay from the cells with Dab1 which also displayed the effect on APP processing. These data suggested that Fe65 and Dab1 compete for binding to APP. Surprisingly, we found that Fe65 interacts with Dab1 via C-terminal region of Dab1 and unphosphorylated Dab1 is capable of binding Fe65. Dab1 interacts with the low-density lipoprotein receptor-related protein (LRP) as well as APP through its PTB domain. Dab1 significantly decreased the amount of APP bound to LRP and the level of secreted APP and APP-CTF in LRP expressing cells, unlike Fe65. It implies that overexpression of Dab1 diminish LRP-APP complex formation, resulting in altered APP processing. The competition for overlapped binding site among adaptor proteins may be related to the regulation mechanism of APP metabolism in various conditions.
Kwon
Oh Yeun
OY
Biomedical Research Center, Korea Institute of Science and Technology, Seongbuk-gu, Seoul 136-791, Korea.
Hwang
Kyounghee
K
Kim
Jeom-A
JA
Kim
Kwangmyung
K
Kwon
Ick Chan
IC
Song
Hyun Kyu
HK
Jeon
Hyesung
H
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding
C091042:APBB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C115785:DAB1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins