title: Disulfide-linked head-to-head multimerization in the mechanism of ion channel clustering by PSD-95.
abstract: The PSD-95/SAP90 family of PDZ-containing proteins is directly involved in the clustering of specific ion channels at synapses. We report that channel clustering depends on a conserved N-terminal domain of PSD-95 that mediates multimerization and disulfide linkage of PSD-95 protomers. This N-terminal multimerization domain confers channel clustering activity on a single PDZ domain. Thus, channel clustering depends on aggregation of PDZ domains achieved by head-to-head multimerization of PSD-95, rather than by concatenation of PDZ domains in PSD-95 monomers. This mechanism predicts that PSD-95 can organize heterogeneous membrane protein clusters via differential binding specificities of its three PDZ domains. PSD-95 and its relative chapsyn-110 exist as disulfide-linked complexes in rat brain, consistent with head-to-head multimerization of these proteins in vivo.
authors.affiliation: Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston 02214, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: Hsueh
authors.forename: E
authors.initials: E
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000818:Animals; D019556:COS Cells / Q000737:chemistry / Q000502:physiology; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D017353:Gene Deletion; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D051637:Shaker Superfamily of Potassium Channels; D014162:Transfection; D025521:Tumor Suppressor Proteins
chemical_list: D003432:Cross-Linking Reagents; D000076122:Disks Large Homolog 4 Protein; D004220:Disulfides; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; C501451:Mpp2 protein, rat; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D051637:Shaker Superfamily of Potassium Channels; D025521:Tumor Suppressor Proteins; C033652:postsynaptic density proteins; D009703:Nucleoside-Phosphate Kinase; C496468:DLG2 protein, human; D051528:Guanylate Kinases