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Phosphorylation of the amino‐terminal region of X11L regulates its interaction with APP
Author(s) -
Sakuma Megumi,
Tanaka Emi,
Taru Hidenori,
Tomita Susumu,
Gandy Sam,
Nairn Angus C.,
Nakaya Tadashi,
Yamamoto Tohru,
Suzuki Toshiharu
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.05988.x
Subject(s) - phosphorylation , amino acid , cytoplasm , signal transducing adaptor protein , microbiology and biotechnology , residue (chemistry) , phosphotyrosine binding domain , biochemistry , c terminus , chemistry , plasma protein binding , biology , sh2 domain , receptor tyrosine kinase
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 (X11L 221–250 ) 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 X11L 221–250 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 X11L 221–250 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.