title: Intracellular membrane targeting and suppression of Ser880 phosphorylation of glutamate receptor 2 by the linker I-set II domain of AMPA receptor-binding protein.
abstract: AMPA receptor-binding protein (ABP) is a multi-postsynaptic density-95/discs large/zona occludens (PDZ) protein that binds to the glutamate receptor 2/3 (GluR2/3) subunits of the AMPA receptor and is implicated in receptor membrane anchorage. A palmitoylated form of ABP localizes to spine heads, whereas a nonpalmitoylated form is found in intracellular clusters. Here, we investigate intracellular cluster formation by ABP and the ability of ABP to associate with GluR2 while in these clusters. We show that ABP interacts with intracellular membranes via the ABP linker I (LI)-set II (SII) subdomain, a region consisting of ABP linker 1 and PDZ4, -5, and -6. This suggests that cluster formation results from LI-SII ABP association with the membrane of a vesicular structure. We present evidence that ABP can self-associate at intracellular membrane surfaces via interactions involving SII. ABP in such membrane clusters can bind and retain GluR2 that has trafficked endocytotically from the plasma membrane. Phosphorylation of GluR2 at serine 880, proximal to the ABP binding site, has been implicated by others in the release of ABP from GluR2 and the mobilization of AMPA receptors for trafficking. We show that binding of GluR2 to ABP blocks phosphorylation of serine 880. This suggests that ABP can stabilize its own association with GluR2. We discuss a model in which ABP can form a protein scaffold at a vesicular membrane that is capable of binding GluR2, leading to formation of an intracellular AMPA receptor pool. Receptors in such a pool may contribute to receptor endocytotic and exocytotic trafficking and recycling.
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.forename: Sunita
authors.initials: S
authors.lastname: deSouza
authors.forename: Edward B
authors.initials: EB
authors.lastname: Ziff
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007425:Intracellular Membranes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C485566:GRIP2 protein, human; C118486:Grip2 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D012694:Serine; D011493:Protein Kinase C; C104722:glutamate receptor ionotropic, AMPA 2