title: Ion channel clustering by membrane-associated guanylate kinases. Differential regulation by N-terminal lipid and metal binding motifs.
abstract: The postsynaptic density protein PSD-95 and related membrane-associated guanylate kinase (MAGUK) proteins assemble signal transduction complexes at sites of cell-cell contact including synapses. Whereas PSD-95 and PSD-93 occur only at postsynaptic sites in hippocampal neurons, SAP-102 also occurs in axons. In heterologous cells, PSD-95 and PSD-93 mediate cell surface ion channel clustering, but SAP-102 and SAP-97 do not. This selective ion channel clustering activity by MAGUKs is explained by differential palmitoylation, as PSD-93 and PSD-95 are palmitoylated though SAP-97, and SAP-102 are not. Rather than being palmitoylated, we find that N-terminal cysteines from SAP-102 tightly bind to zinc. And, appending the N terminus of SAP-102 to PSD-95 results in localization of the chimera to both axons and dendrites. These data suggest that lipid modifications and heavy metal associations with the N termini of MAGUKs mediate differential functions and subcellular localizations of these synaptic scaffolds.
authors.affiliation: Departments of Physiology and University of California, San Francisco, California 94143, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: El-Husseini
authors.forename: J R
authors.initials: JR
authors.lastname: Topinka
authors.forename: J E
authors.initials: JE
authors.lastname: Lehrer-Graiwer
authors.forename: B L
authors.initials: BL
authors.lastname: Firestein
authors.forename: S E
authors.initials: SE
authors.lastname: Craven
authors.forename: C
authors.initials: C
authors.lastname: Aoki
authors.forename: D S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005455:Fluorescent Antibody Technique; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000302:isolation & purification / Q000378:metabolism*; D009479:Neuropeptides / Q000302:isolation & purification / Q000378:metabolism; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D019308:Palmitic Acid; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000076122:Disks Large Homolog 4 Protein; C501119:Dlg1 protein, rat; C101195:Dlg3 protein, rat; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D008074:Lipoproteins; D008565:Membrane Proteins; C501451:Mpp2 protein, rat; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C033652:postsynaptic density proteins; D019308:Palmitic Acid; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D015032:Zinc