title: Phosphorylation of the amino-terminal region of X11L regulates its interaction with APP.
abstract: X11-like (X11L) is neuronal adaptor protein that interacts with the amyloid beta-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.
authors.affiliation: Hokkaido University, Kita-ku, Sapporo, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sakuma
authors.forename: Emi
authors.initials: E
authors.lastname: Tanaka
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.forename: Susumu
authors.initials: S
authors.lastname: Tomita
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism* / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary
chemical_list: C491636:APBA2 protein, human; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins