title: Identification of an intramolecular interaction between the SH3 and guanylate kinase domains of PSD-95.
abstract: Postsynaptic density-95 (PSD-95/SAP-90) is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins that assemble protein complexes at synapses and other cell junctions. MAGUKs comprise multiple protein-protein interaction motifs including PDZ, SH3 and guanylate kinase (GK) domains, and these binding sites mediate the scaffolding function of MAGUK proteins. Synaptic binding partners for the PDZ and GK domains of PSD-95 have been identified, but the role of the SH3 domain remains elusive. We now report that the SH3 domain of PSD-95 mediates a specific interaction with the GK domain. The GK domain lacks a poly-proline motif that typically binds to SH3 domains; instead, SH3/GK binding is a bi-domain interaction that requires both intact motifs. Although isolated SH3 and GK domains can bind in trans, experiments with intact PSD-95 molecules indicate that intramolecular SH3/GK binding dominates and prevents intermolecular associations. SH3/GK binding is conserved in the related Drosophila MAGUK protein DLG but is not detectable for Caenorhabditis elegans LIN-2. Many previously identified genetic mutations of MAGUKs in invertebrates occur in the SH3 or GK domains, and all of these mutations disrupt intramolecular SH3/GK binding.
authors.affiliation: Department of Physiology and Program in Neuroscience, University of California at San Francisco, San Francisco, California 94143-0444, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: McGee
authors.forename: D S
authors.initials: DS
authors.lastname: Bredt
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005656:Fungal Proteins / Q000235:genetics; D051528:Guanylate Kinases; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D019476:Insect Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D000074407:SAP90-PSD95 Associated Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000235:genetics; D014170:Transformation, Genetic; D025521:Tumor Suppressor Proteins; D015003:Yeasts / Q000235:genetics; D018909:src Homology Domains / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D015801:Helminth Proteins; D019476:Insect Proteins; C097978:Lin-2 protein, C elegans; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C033652:postsynaptic density proteins; C070350:dlg1 protein, Drosophila; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases