title: Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling.
abstract: The phosphorylation of Tyr-682 residue in the intracellular domain (AID) of amyloid-beta protein precursor (AbetaPP) is significantly enhanced in Alzheimer's disease patients' brain. The role of this phosphotyrosine, however, remains elusive. Here we report that phosphorylation of Tyr-682 inhibits the interactions between AbetaPP and Fe65, which is the main regulatory mechanism controlling Fe65 nuclear signaling. Furthermore, we show that tyrosine phosphorylation of AbetaPP also inhibits interaction of the two other Fe65 family members, Fe65L1 and Fe65L2. Likewise, docking of Fe65, Fe65L1 and Fe65L2 to APLP1 and APLP2, the two other members of the AbetaPP-gene family, is abolished by analogous phosphorylation events. Our results indicate that phosphorylation of the cytoplasmic tail of AbetaPP on Tyr-682 represents a second mechanism, alternative to AbetaPP processing by secretases, that regulates AbetaPP/Fe65 downstream signaling pathways.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D020349:Surface Plasmon Resonance / Q000379:methods; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
chemical_list: C091042:APBB1 protein, human; C489697:APLP1 protein, human; C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014443:Tyrosine