Phosphorylation of the amino-terminal region of X11L regulates its interaction with APP |
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Authors: | Megumi Sakuma,Emi Tanaka,Hidenori Taru&dagger ,Susumu Tomita&Dagger ,Sam Gandy§ ,Angus C. Nairn¶ ,Tadashi Nakaya,Tohru Yamamoto, Toshiharu Suzuki |
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Affiliation: | Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan; Laboratory of Neuronal Cell Biology, Graduate School of Pharmaceutical Sciences and Creative Research Institute, Hokkaido University, Kita-ku, Sapporo, Japan; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA; Mount Sinai School of Medicine, Alzheimer's Research Center, New York, USA; Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities, New Haven, Connecticut, USA |
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Abstract: | X11-like (X11L) is neuronal adaptor protein that interacts with the amyloid β-protein precursor (APP) and regulates its metabolism. The phosphotyrosine interaction/binding (PI/PTB) domain of X11L interacts with the cytoplasmic region of APP695. We found that X11L–APP interaction is enhanced in osmotically stressed cells and X11L modification is required for the enhancement. Amino acids 221–250 (X11L221–250) are required for the enhanced association with APP in osmotically stressed cells; this motif is 118 amino acids closer to the amino-terminal end of the protein than the PI/PTB domain (amino acids 368–555). We identified two phosphorylatable seryl residues, Ser236 and Ser238, in X11L221–250 and alanyl substitution of either seryl residue diminished the enhanced association with APP. In brain Ser238 was found to be phosphorylated and phosphorylation of X11L was required for the interaction of X11L and APP. Both seryl residues in X11L221–250 are conserved in neuronal X11, but not in X11L2, a non-neuronal X11 family member that did not exhibit enhanced APP association in osmotically stressed cells. These findings indicate that the region of X11L that regulates association with APP is located outside of, and amino-terminal to, the PI/PTB domain. Modification of this regulatory region may alter the conformation of the PI/PTB domain to modulate APP binding. |
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Keywords: | Alzheimer's disease amyloid β-protein precursor cell stress protein phosphorylation X11 X11-like |
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