G2Cdb::Gene report

Gene id
G00002118
Gene symbol
DLGAP1 (HGNC)
Species
Homo sapiens
Description
discs, large (Drosophila) homolog-associated protein 1
Orthologue
G00000869 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000068212 (Vega human gene)
Gene
ENSG00000170579 (Ensembl human gene)
9229 (Entrez Gene)
37 (G2Cdb plasticity & disease)
DLGAP1 (GeneCards)
Literature
605445 (OMIM)
Marker Symbol
HGNC:2905 (HGNC)
Protein Sequence
O14490 (UniProt)

Synonyms (3)

  • DAP-1
  • GKAP
  • SAPAP1

Diseases (2)

Disease Nervous effect Mutations Found Literature Mutations Type Genetic association?
D00000166: Schizophrenia Y Y (12950712) Single nucleotide polymorphism (SNP) N
D00000228: Myopia N Y (15723005) Polymorphism (P) N
D00000228: Myopia N Y (15723005) Microinsertion (MI) N

References

  • Genomic structure and organization of the high grade Myopia-2 locus (MYP2) critical region: mutation screening of 9 positional candidate genes.

    Scavello GS, Paluru PC, Zhou J, White PS, Rappaport EF and Young TL

    Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

    Purpose: Myopia is a common complex eye disorder, with implications for blindness due to increased risk of retinal detachment, chorioretinal degeneration, premature cataracts, and glaucoma. A genomic interval of 2.2 centiMorgans (cM) was defined on chromosome band 18p11.31 using 7 families diagnosed with autosomal dominant high myopia and was designated the MYP2 locus. To characterize this region, we analyzed 9 known candidate genes localized to within the 2.2 cM interval by direct sequencing.

    Methods: Using public databases, a physical map of the MYP2 interval was compiled. Gene expression studies in ocular tissues using complementary DNA library screens, microarray experiments, reverse transcription techniques, and expression data identified in external databases aided in prioritizing gene selection for screening. Coding regions, intron-exon boundaries and untranslated exons of all known genes [Clusterin-like 1 (CLUL1), elastin microfibril interfacer 2 (EMILIN2), lipin 2 (LPIN2), myomesin 1 (MYOM1), myosin regulatory light chain 3 (MRCL3), myosin regulatory light chain 2 (MRLC2), transforming growth beta-induced factor (TGIFbeta), large Drosophila homolog associated protein 1 (DLGAP1), and zinc finger protein 161 homolog (ZFP161)] were sequenced using genomic DNA samples from 9 affected and 6 unaffected MYP2 pedigree members, and from 5 external controls (4 unaffected and 1 affected). Gene sequence changes were compared to known variants from public single nucleotide polymorphism (SNP) databases.

    Results: In total, 103 polymorphisms were found by direct sequencing; 10 were missense, 14 were silent, 26 were not translated, 49 were intronic, 1 insertion, and 3 were homozygous deletions. Twenty-seven polymorphisms were novel. Novel SNPs were submitted to the public database; observed frequencies were submitted for known SNPs. No sequence alterations segregated with the disease phenotype.

    Conclusions: Mutation analysis of 9 encoded positional candidate genes on MYP2 loci did not identify sequence alterations associated with the disease phenotype. Further studies of MYP2 candidate genes, including analysis of putative genes predicted in silico, are underway.

    Funded by: BHP HRSA HHS: 2PEY01583-26; NEI NIH HHS: EY00376

    Molecular vision 2005;11;97-110

  • Mutation and association analysis of the DAP-1 gene with schizophrenia.

    Aoyama S, Shirakawa O, Ono H, Hashimoto T, Kajimoto Y and Maeda K

    Department of Environmental Health and Safety, Kobe University Graduate School of Medicine, Kobe, Japan.

    Glutamate dysfunction has been hypothesized to be involved in the pathophysiology of schizophrenia. The human homolog of Drosophila discs large protein (hDLG) and post-synaptic density-95-associated protein-1 (DAP-1) is one of the major proteins that are involved in intracellular signal transduction via N-methyl-d-aspartate receptors. In the present study 33 Japanese patients with schizophrenia were screened for mutations in the DAP-1 gene. A single nucleotide polymorphism was identified in the DAP-1 gene (1618A/G). A case-control study using a larger sample of unrelated patients and controls did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the DAP-1 gene is involved in vulnerability to schizophrenia.

    Psychiatry and clinical neurosciences 2003;57;5;545-7

Literature (20)

Pubmed - human_disease

  • Genomic structure and organization of the high grade Myopia-2 locus (MYP2) critical region: mutation screening of 9 positional candidate genes.

    Scavello GS, Paluru PC, Zhou J, White PS, Rappaport EF and Young TL

    Division of Ophthalmology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

    Purpose: Myopia is a common complex eye disorder, with implications for blindness due to increased risk of retinal detachment, chorioretinal degeneration, premature cataracts, and glaucoma. A genomic interval of 2.2 centiMorgans (cM) was defined on chromosome band 18p11.31 using 7 families diagnosed with autosomal dominant high myopia and was designated the MYP2 locus. To characterize this region, we analyzed 9 known candidate genes localized to within the 2.2 cM interval by direct sequencing.

    Methods: Using public databases, a physical map of the MYP2 interval was compiled. Gene expression studies in ocular tissues using complementary DNA library screens, microarray experiments, reverse transcription techniques, and expression data identified in external databases aided in prioritizing gene selection for screening. Coding regions, intron-exon boundaries and untranslated exons of all known genes [Clusterin-like 1 (CLUL1), elastin microfibril interfacer 2 (EMILIN2), lipin 2 (LPIN2), myomesin 1 (MYOM1), myosin regulatory light chain 3 (MRCL3), myosin regulatory light chain 2 (MRLC2), transforming growth beta-induced factor (TGIFbeta), large Drosophila homolog associated protein 1 (DLGAP1), and zinc finger protein 161 homolog (ZFP161)] were sequenced using genomic DNA samples from 9 affected and 6 unaffected MYP2 pedigree members, and from 5 external controls (4 unaffected and 1 affected). Gene sequence changes were compared to known variants from public single nucleotide polymorphism (SNP) databases.

    Results: In total, 103 polymorphisms were found by direct sequencing; 10 were missense, 14 were silent, 26 were not translated, 49 were intronic, 1 insertion, and 3 were homozygous deletions. Twenty-seven polymorphisms were novel. Novel SNPs were submitted to the public database; observed frequencies were submitted for known SNPs. No sequence alterations segregated with the disease phenotype.

    Conclusions: Mutation analysis of 9 encoded positional candidate genes on MYP2 loci did not identify sequence alterations associated with the disease phenotype. Further studies of MYP2 candidate genes, including analysis of putative genes predicted in silico, are underway.

    Funded by: BHP HRSA HHS: 2PEY01583-26; NEI NIH HHS: EY00376

    Molecular vision 2005;11;97-110

Pubmed - other

  • Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.

    Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, Jia CY, Jurisica I and Li SS

    Department of Biochemistry and the Siebens-Drake Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

    Systematic identification of direct protein-protein interactions is often hampered by difficulties in expressing and purifying the corresponding full-length proteins. By taking advantage of the modular nature of many regulatory proteins, we attempted to simplify protein-protein interactions to the corresponding domain-ligand recognition and employed peptide arrays to identify such binding events. A group of 12 Src homology (SH) 3 domains from eight human proteins (Swiss-Prot ID: SRC, PLCG1, P85A, NCK1, GRB2, FYN, CRK) were used to screen a peptide target array composed of 1536 potential ligands, which led to the identification of 921 binary interactions between these proteins and 284 targets. To assess the efficiency of the peptide array target screening (PATS) method in identifying authentic protein-protein interactions, we examined a set of interactions mediated by the PLCgamma1 SH3 domain by coimmunoprecipitation and/or affinity pull-downs using full-length proteins and achieved a 75% success rate. Furthermore, we characterized a novel interaction between PLCgamma1 and hematopoietic progenitor kinase 1 (HPK1) identified by PATS and demonstrated that the PLCgamma1 SH3 domain negatively regulated HPK1 kinase activity. Compared to protein interactions listed in the online predicted human interaction protein database (OPHID), the majority of interactions identified by PATS are novel, suggesting that, when extended to the large number of peptide interaction domains encoded by the human genome, PATS should aid in the mapping of the human interactome.

    Proteomics 2007;7;11;1775-85

  • p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP.

    Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Centeno F, Goedert M, Morrice NA and Cuenda A

    MRC Protein Phosphorylation Unit, University of Dundee, Dundee, UK.

    Activation of the p38 MAP kinase pathways is crucial for the adaptation of mammalian cells to changes in the osmolarity of the environment. Here we identify SAP97/hDlg, the mammalian homologue of the Drosophila tumour suppressor Dlg, as a physiological substrate for the p38gamma MAP kinase (SAPK3/p38gamma) isoform. SAP97/hDlg is a scaffold protein that forms multiprotein complexes with a variety of proteins and is targeted to the cytoskeleton by its association with the protein guanylate kinase-associated protein (GKAP). The SAPK3/p38gamma-catalysed phosphorylation of SAP97/hDlg triggers its dissociation from GKAP and therefore releases it from the cytoskeleton. This is likely to regulate the integrity of intercellular-junctional complexes, and cell shape and volume in response to osmotic stress.

    The EMBO journal 2005;24;6;1134-45

  • A novel scaffold protein, TANC, possibly a rat homolog of Drosophila rolling pebbles (rols), forms a multiprotein complex with various postsynaptic density proteins.

    Suzuki T, Li W, Zhang JP, Tian QB, Sakagami H, Usuda N, Usada N, Kondo H, Fujii T and Endo S

    Department of Neuroplasticity, Institute on Ageing and Adaptation, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. suzukit@sch.md.shinshu-u.ac.jp

    We cloned from the rat brain a novel gene, tanc (GenBank Accession No. AB098072), which encoded a protein containing three tetratricopeptide repeats (TPRs), ten ankyrin repeats and a coiled-coil region, and is possibly a rat homolog of Drosophila rolling pebbles (rols). The tanc gene was expressed widely in the adult rat brain. Subcellular distribution, immunohistochemical study of the brain and immunocytochemical studies of cultured neuronal cells indicated the postsynaptic localization of TANC protein of 200 kDa. Pull-down experiments showed that TANC protein bound PSD-95, SAP97, and Homer via its C-terminal PDZ-binding motif, -ESNV, and fodrin via both its ankyrin repeats and the TPRs together with the coiled-coil domain. TANC also bound the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. An immunoprecipitation study showed TANC association with various postsynaptic proteins, including guanylate kinase-associated protein (GKAP), alpha-internexin, and N-methyl-D-aspartate (NMDA)-type glutamate receptor 2B and AMPA-type glutamate receptor (GluR1) subunits. These results suggest that TANC protein may work as a postsynaptic scaffold component by forming a multiprotein complex with various postsynaptic density proteins.

    The European journal of neuroscience 2005;21;2;339-50

  • Phosphoproteomic analysis of the developing mouse brain.

    Ballif BA, Villén J, Beausoleil SA, Schwartz D and Gygi SP

    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.

    Proper development of the mammalian brain requires the precise integration of numerous temporally and spatially regulated stimuli. Many of these signals transduce their cues via the reversible phosphorylation of downstream effector molecules. Neuronal stimuli acting in concert have the potential of generating enormous arrays of regulatory phosphoproteins. Toward the global profiling of phosphoproteins in the developing brain, we report here the use of a mass spectrometry-based methodology permitting the first proteomic-scale phosphorylation site analysis of primary animal tissue, identifying over 500 protein phosphorylation sites in the developing mouse brain.

    Funded by: NHGRI NIH HHS: HG00041

    Molecular & cellular proteomics : MCP 2004;3;11;1093-101

  • Crystal structure of the Shank PDZ-ligand complex reveals a class I PDZ interaction and a novel PDZ-PDZ dimerization.

    Im YJ, Lee JH, Park SH, Park SJ, Rho SH, Kang GB, Kim E and Eom SH

    Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, South Korea.

    The Shank/proline-rich synapse-associated protein family of multidomain proteins is known to play an important role in the organization of synaptic multiprotein complexes. For instance, the Shank PDZ domain binds to the C termini of guanylate kinase-associated proteins, which in turn interact with the guanylate kinase domain of postsynaptic density-95 scaffolding proteins. Here we describe the crystal structures of Shank1 PDZ in its peptide free form and in complex with the C-terminal hexapeptide (EAQTRL) of guanylate kinase-associated protein (GKAP1a) determined at 1.8- and 2.25-A resolutions, respectively. The structure shows the typical class I PDZ interaction of PDZ-peptide complex with the consensus sequence -X-(Thr/Ser)-X-Leu. In addition, Asp-634 within the Shank1 PDZ domain recognizes the positively charged Arg at -1 position and hydrogen bonds, and salt bridges between Arg-607 and the side chains of the ligand at -3 and -5 positions contribute further to the recognition of the peptide ligand. Remarkably, whether free or complexed, Shank1 PDZ domains form dimers with a conserved beta B/beta C loop and N-terminal beta A strands, suggesting a novel model of PDZ-PDZ homodimerization. This implies that antiparallel dimerization through the N-terminal beta A strands could be a common configuration among PDZ dimers. Within the dimeric structure, the two-peptide binding sites are arranged so that the N termini of the bound peptide ligands are in close proximity and oriented toward the 2-fold axis of the dimer. This configuration may provide a means of facilitating dimeric organization of PDZ-target assemblies.

    The Journal of biological chemistry 2003;278;48;48099-104

  • Mutation and association analysis of the DAP-1 gene with schizophrenia.

    Aoyama S, Shirakawa O, Ono H, Hashimoto T, Kajimoto Y and Maeda K

    Department of Environmental Health and Safety, Kobe University Graduate School of Medicine, Kobe, Japan.

    Glutamate dysfunction has been hypothesized to be involved in the pathophysiology of schizophrenia. The human homolog of Drosophila discs large protein (hDLG) and post-synaptic density-95-associated protein-1 (DAP-1) is one of the major proteins that are involved in intracellular signal transduction via N-methyl-d-aspartate receptors. In the present study 33 Japanese patients with schizophrenia were screened for mutations in the DAP-1 gene. A single nucleotide polymorphism was identified in the DAP-1 gene (1618A/G). A case-control study using a larger sample of unrelated patients and controls did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the DAP-1 gene is involved in vulnerability to schizophrenia.

    Psychiatry and clinical neurosciences 2003;57;5;545-7

  • The 8-kDa dynein light chain binds to its targets via a conserved (K/R)XTQT motif.

    Lo KW, Naisbitt S, Fan JS, Sheng M and Zhang M

    Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People's Republic of China.

    Cytoplasmic dynein is a large, multisubunit molecular motor that translocates cargoes toward the minus ends of microtubules. Proper functioning of the dynein motor requires precise assembly of its various subunits. Using purified recombinant proteins, we show that the highly conserved 8-kDa light chain (DLC8) binds to the intermediate chain of the dynein complex. The DLC8-binding region was mapped to a highly conserved 10-residue fragment (amino acid sequence SYSKETQTPL) C-terminal to the second alternative splicing site of dynein intermediate chain. Yeast two-hybrid screening using DLC8 as bait identified numerous additional DLC8-binding proteins. Biochemical and mutational analysis of selected DLC8-binding proteins revealed that DLC8 binds to a consensus sequence containing a (K/R)XTQT motif. The (K/R)XTQT motif interacts with the common target-accepting grooves of DLC8 dimer. The role of each conserved amino acid residue in this pentapeptide motif in supporting complex formation with DLC8 was systematically studied using site-directed mutagenesis.

    The Journal of biological chemistry 2001;276;17;14059-66

  • Intramolecular interactions regulate SAP97 binding to GKAP.

    Wu H, Reissner C, Kuhlendahl S, Coblentz B, Reuver S, Kindler S, Gundelfinger ED and Garner CC

    University of Alabama at Birmingham, Department of Neurobiology, 1719 Sixth Avenue South CIRC 589, Birmingham, AL 35294-0021, USA.

    Membrane-associated guanylate kinase homologs (MAGUKs) are multidomain proteins found to be central organizers of cellular junctions. In this study, we examined the molecular mechanisms that regulate the interaction of the MAGUK SAP97 with its GUK domain binding partner GKAP (GUK-associated protein). The GKAP-GUK interaction is regulated by a series of intramolecular interactions. Specifically, the association of the Src homology 3 (SH3) domain and sequences situated between the SH3 and GUK domains with the GUK domain was found to interfere with GKAP binding. In contrast, N-terminal sequences that precede the first PDZ domain in SAP97, facilitated GKAP binding via its association with the SH3 domain. Utilizing crystal structure data available for PDZ, SH3 and GUK domains, molecular models of SAP97 were generated. These models revealed that SAP97 can exist in a compact U-shaped conformation in which the N-terminal domain folds back and interacts with the SH3 and GUK domains. These models support the biochemical data and provide new insights into how intramolecular interactions may regulate the association of SAP97 with its binding partners.

    Funded by: NIA NIH HHS: AG 06569-09, AG 12978-02; NICHD NIH HHS: P50 HD32901

    The EMBO journal 2000;19;21;5740-51

  • The hDLG-associated protein DAP interacts with dynein light chain and neuronal nitric oxide synthase.

    Haraguchi K, Satoh K, Yanai H, Hamada F, Kawabuchi M and Akiyama T

    Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Japan.

    Background: Postsynaptic density (PSD)-95 interacts with and mediates clustering of the N-methyl-D-aspartate-receptors (NMDA-R). PSD-95 also interacts with the hDLG-associated protein DAP, which is also called Synapse-associated protein 90-associated protein (SAPAP), and Guanylate kinase-associated protein (GKAP).

    Results: DAP interacted directly with the dynein light chain (DLC) family of proteins. DLC was contained in the NMDA-R-PSD-95-DAP-neuronal nitric oxide synthase (nNOS) complex. Furthermore, DAP interacted with nNOS and recruited it into the Triton X-100-insoluble fraction of transfected cells.

    Conclusion: DAP interacts directly with DLC and nNOS, and links these proteins to the NMDA-R-PSD-95 complex.

    Genes to cells : devoted to molecular & cellular mechanisms 2000;5;11;905-911

  • Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein.

    Naisbitt S, Valtschanoff J, Allison DW, Sala C, Kim E, Craig AM, Weinberg RJ and Sheng M

    Howard Hughes Medical Institute, Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

    NMDA receptors interact directly with postsynaptic density-95 (PSD-95), a scaffold protein that organizes a cytoskeletal- signaling complex at the postsynaptic membrane. The molecular mechanism by which the PSD-95-based protein complex is trafficked to the postsynaptic site is unknown but presumably involves specific motor proteins. Here we demonstrate a direct interaction between the PSD-95-associated protein guanylate kinase domain-associated protein (GKAP) and dynein light chain (DLC), a light chain subunit shared by myosin-V (an actin-based motor) and cytoplasmic dynein (a microtubule-based motor). A yeast two-hybrid screen with GKAP isolated DLC2, a novel protein 93% identical to the previously cloned 8 kDa dynein light chain (DLC1). A complex containing PSD-95, GKAP, DLC, and myosin-V can be immunoprecipitated from rat brain extracts. DLC colocalizes with PSD-95 and F-actin in dendritic spines of cultured neurons and is enriched in biochemical purifications of PSD. Immunogold electron microscopy reveals a concentration of DLC in the postsynaptic compartment of asymmetric synapses of brain in which it is associated with the PSD and the spine apparatus. We discuss the possibility that the GKAP/DLC interaction may be involved in trafficking of the PSD-95 complex by motor proteins.

    Funded by: NINDS NIH HHS: NS29879, NS33184, NS35050

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2000;20;12;4524-34

  • nArgBP2, a novel neural member of ponsin/ArgBP2/vinexin family that interacts with synapse-associated protein 90/postsynaptic density-95-associated protein (SAPAP).

    Kawabe H, Hata Y, Takeuchi M, Ide N, Mizoguchi A and Takai Y

    Department of Molecular Biology, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan.

    Postsynaptic density (PSD)-95/synapse-associated protein (SAP) 90 and synaptic scaffolding molecule (S-SCAM) are synaptic membrane-associated guanylate kinases. Both the proteins interact with SAP90/PSD-95-associated protein (SAPAP) (also called guanylate kinase-associated protein/Dlg-associated protein). SAPAP is a protein highly enriched in the PSD fraction and may link PSD-95/SAP90 and S-SCAM to Triton X-100-insoluble structures. We found here a novel SAPAP-interacting protein, which was specifically expressed in neural tissue and was present in the postsynaptic density fraction in brain. This protein had a sorbin homology domain in the N terminus, a zinc finger motif in the middle region, and three src homology (SH) 3 domains in the C terminus and was homologous to the ponsin/ArgBP2/vinexin family proteins. We named this protein nArgBP2 because it was the most homologous to ArgBP2. nArgBP2 is a neural member of a growing family of SH3-containing proteins. nArgBP2 bound to the proline-rich region of SAPAP via its third SH3 domain and was coimmunoprecipitated with SAPAP from the extract of rat brain. Furthermore, nArgBP2 was colocalized with SAPAP at synapses in cerebellum. nArgBP2 bound to not only SAPAP but also vinculin and l-afadin, known to bind to ponsin and vinexin. nArgBP2 may be implicated in the protein network around SAPAP in the PSD.

    The Journal of biological chemistry 1999;274;43;30914-8

  • Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family.

    Boeckers TM, Winter C, Smalla KH, Kreutz MR, Bockmann J, Seidenbecher C, Garner CC and Gundelfinger ED

    Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg, 39118, Germany. bockers@uni-muenster.de

    We have recently isolated a novel proline-rich synapse-associated protein-1 (ProSAP1) that is highly enriched in postsynaptic density (PSD). A closely related multidomain protein, ProSAP2, shares a highly conserved PDZ (PSD-95/discs-large/ZO-1) domain (80% identity), a ppI domain that mediates the interaction with cortactin, and a C-terminal SAM (sterile alpha-motif) domain. In addition, ProSAP2 codes for five ankyrin repeats and a SH3 (Src homology 3) domain. Transcripts for both proteins are coexpressed in many regions of rat brain, but show a distinct expression pattern in the cerebellum. Using the PDZ domains of ProSAP1 and 2 as bait in the yeast two-hybrid system, we isolated several clones of the SAPAP/GKAP (SAP90/PSD-95-associated protein/guanylate kinase-associated protein) family. The association of the proteins was verified by coimmunoprecipitation and cotransfection in HEK cells. Therefore, proteins of the ProSAP family represent a novel link between SAP90/PSD-95 bound membrane receptors and the cytoskeleton at glutamatergic synapses of the central nervous system.

    Funded by: NIA NIH HHS: AG12978-02; NICHD NIH HHS: P50 HD32901

    Biochemical and biophysical research communications 1999;264;1;247-52

  • BEGAIN (brain-enriched guanylate kinase-associated protein), a novel neuronal PSD-95/SAP90-binding protein.

    Deguchi M, Hata Y, Takeuchi M, Ide N, Hirao K, Yao I, Irie M, Toyoda A and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.

    PSD-95/SAP90 is a synaptic membrane-associated guanylate kinase with three PDZ, one SH3, and one guanylate kinase (GK) domain. PSD-95/SAP90 binds various proteins through the PDZ domains and organizes synaptic junctions. PSD-95/SAP90 also interacts with the postsynaptic density (PSD) fraction-enriched protein, named SAPAP (also called GKAP and DAP), through the GK domain. SAPAP is Triton X-100-insoluble and recruits PSD-95/SAP90 into the Triton X-100-insoluble fraction in the transfected cells, suggesting that SAPAP may fix PSD-95/SAP90 to the PSD. Here we report a novel protein interacting with the GK domain of PSD-95/SAP90, BEGAIN. BEGAIN is specifically expressed in brain and enriched in the PSD fraction. BEGAIN is Triton X-100-soluble in the transfected cells but is recruited to the Triton X-100-insoluble fraction by SAPAP when coexpressed with PSD-95/SAP90. BEGAIN may be a novel PSD component associated with the core complex of PSD-95/SAP90 and SAPAP.

    The Journal of biological chemistry 1998;273;41;26269-72

  • A novel multiple PDZ domain-containing molecule interacting with N-methyl-D-aspartate receptors and neuronal cell adhesion proteins.

    Hirao K, Hata Y, Ide N, Takeuchi M, Irie M, Yao I, Deguchi M, Toyoda A, Sudhof TC and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co. Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan.

    At synaptic junctions, pre- and postsynaptic membranes are connected by cell adhesion and have distinct structures for specialized functions. The presynaptic membranes have a machinery for fast neurotransmitter release, and the postsynaptic membranes have clusters of neurotransmitter receptors. The molecular mechanism of the assembly of synaptic junctions is not yet clear. Pioneering studies identified postsynaptic density (PSD)-95/SAP90 as a prototypic synaptic scaffolding protein to maintain the structure of synaptic junctions. PSD-95/SAP90 belongs to a family of membrane-associated guanylate kinases and binds N-methyl-D-aspartate receptors, potassium channels, and neuroligins through the PDZ domains and GKAP/SAPAP/DAP through the guanylate kinase (GK) domain. We performed here a yeast two-hybrid screening for SAPAP-interacting molecules and identified a novel protein that has an inverse structure of membrane-associated guanylate kinases with an NH2-terminal GK-like domain followed by two WW and five PDZ domains. It binds SAPAP through the GK-like domain and NMDA receptors and neuroligins through the PDZ domains. We named this protein S-SCAM (synaptic scaffolding molecule) because S-SCAM may assemble receptors and cell adhesion proteins at synaptic junctions.

    The Journal of biological chemistry 1998;273;33;21105-10

  • Characterization of guanylate kinase-associated protein, a postsynaptic density protein at excitatory synapses that interacts directly with postsynaptic density-95/synapse-associated protein 90.

    Naisbitt S, Kim E, Weinberg RJ, Rao A, Yang FC, Craig AM and Sheng M

    Howard Hughes Medical Institute and Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachussetts 02114, USA.

    The structure of central synapses is poorly understood at the molecular level. A recent advance came with the identification of the postsynaptic density-95 (PSD-95)/synapse-associated protein 90 family of proteins as important mediators of the synaptic clustering of certain classes of ion channels. By yeast two-hybrid screening, a novel protein termed guanylate kinase-associated protein (GKAP) has been isolated that binds to the GK-like domain of PSD-95 (). Here we present a detailed characterization of GKAP expression in the rat brain and report the cloning of a novel GKAP splice variant. By Northern blot, GKAP mRNAs (4, 6.5, and 8 kB) are expressed predominantly in the rat brain. By in situ hybridization, GKAP is expressed widely in neurons of cortex and hippocampus and in the Purkinje and granule cells of the cerebellum. On brain immunoblots, two prominent bands of 95 and 130 kDa are detected that correspond to products of short and long N-terminal splice variants of GKAP. Two independent GKAP antibodies label somatodendritic puncta in neocortical and hippocampal neurons in a pattern consistent with synaptic elements. Immunogold electron microscopy reveals GKAP to be predominantly postsynaptic and present at asymmetric synapses and in dendritic spines. The distribution of GKAP immunogold particles is uniform in the lateral plane of the PSD but peaks in the perpendicular axis approximately 20 nm from the postsynaptic membrane. In cultured hippocampal neurons GKAP immunoreactive puncta colocalize with the AMPA receptor subunit Glu receptor 1 but not with the GABAA receptor subunits beta2 and beta3. Thus GKAP is a widely expressed neuronal protein localized specifically in the PSD of glutamatergic synapses, consistent with its direct interaction with PSD-95 family proteins.

    Funded by: NINDS NIH HHS: NS29879, NS35050

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1997;17;15;5687-96

  • DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95.

    Satoh K, Yanai H, Senda T, Kohu K, Nakamura T, Okumura N, Matsumine A, Kobayashi S, Toyoshima K and Akiyama T

    Department of Oncogene Research, Institute for Microbial Diseases, Osaka University, Suita, Japan.

    Background: The human homologue of the Drosophila discs large tumour suppressor protein (hDLG) and closely related proteins such as postsynaptic density protein 95 kDa (PSD-95) are associated with N-methyl-D-aspartate receptors (NMDA-R) and Shaker-type K+ channels, and are thought to be involved in their clustering.

    Results: We have identified a protein named DAP-1 that binds to the guanylate kinase-like domains of hDLG and PSD-95. DAP-1 was found to associate with hDLG, PSD-95, NMDA-R and adenomatous polyposis coli protein (APC). Furthermore, we found that DAP-1 is specifically expressed in the brain and colocalizes with PSD-95 and APC in mouse cerebellum. We also found that DAP-1 is colocalized with PSD-95 and NMDA-R at the synapses in cultured rat hippocampal neurons.

    Conclusion: Our findings suggest that DAP-1 may play several roles in the molecular organization of synapses and neuronal cell signalling by interacting with hDLG and PSD-95, which in turn are associated with receptors, ion channels and APC.

    Genes to cells : devoted to molecular & cellular mechanisms 1997;2;6;415-24

  • SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density.

    Takeuchi M, Hata Y, Hirao K, Toyoda A, Irie M and Takai Y

    Takai Biotimer Project, ERATO, Japan Science and Technology Corporation, c/o JCR Pharmaceuticals Co., Ltd., 2-2-10 Murotani, Nishi-ku, Kobe 651-22, Japan.

    PSD-95/SAP90 is a member of membrane-associated guanylate kinases localized at postsynaptic density (PSD) in neuronal cells. Membrane-associated guanylate kinases are a family of signaling molecules expressed at various submembrane domains which have the PDZ (DHR) domains, the SH3 domain, and the guanylate kinase domain. PSD-95/SAP90 interacts with N-methyl-D-aspartate receptors 2A/B, Shaker-type potassium channels, and brain nitric oxide synthase through the PDZ (DHR) domains and clusters these molecules at synaptic junctions. However, neither the function of the SH3 domain or the guanylate kinase domain of PSD-95/SAP90, nor the protein interacting with these domains has been identified. We have isolated here a novel protein family consisting of at least four members which specifically interact with PSD-95/SAP90 and its related proteins through the guanylate kinase domain, and named these proteins SAPAPs (SAP90/PSD-95-Associated Proteins). SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.

    The Journal of biological chemistry 1997;272;18;11943-51

  • GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules.

    Kim E, Naisbitt S, Hsueh YP, Rao A, Rothschild A, Craig AM and Sheng M

    Howard Hughes Medical Institute, Department of Neurobiology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.

    The molecular mechanisms underlying the organization of ion channels and signaling molecules at the synaptic junction are largely unknown. Recently, members of the PSD-95/SAP90 family of synaptic MAGUK (membrane-associated guanylate kinase) proteins have been shown to interact, via their NH2-terminal PDZ domains, with certain ion channels (NMDA receptors and K+ channels), thereby promoting the clustering of these proteins. Although the function of the NH2-terminal PDZ domains is relatively well characterized, the function of the Src homology 3 (SH3) domain and the guanylate kinase-like (GK) domain in the COOH-terminal half of PSD-95 has remained obscure. We now report the isolation of a novel synaptic protein, termed GKAP for guanylate kinase-associated protein, that binds directly to the GK domain of the four known members of the mammalian PSD-95 family. GKAP shows a unique domain structure and appears to be a major constituent of the postsynaptic density. GKAP colocalizes and coimmunoprecipitates with PSD-95 in vivo, and coclusters with PSD-95 and K+ channels/NMDA receptors in heterologous cells. Given their apparent lack of guanylate kinase enzymatic activity, the fact that the GK domain can act as a site for protein-protein interaction has implications for the function of diverse GK-containing proteins (such as p55, ZO-1, and LIN-2/CASK).

    Funded by: NINDS NIH HHS: NS33184, R01 NS033184

    The Journal of cell biology 1997;136;3;669-78

Gene lists (11)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000011 G2C Homo sapiens Human clathrin Human orthologues of mouse clathrin coated vesicle genes adapted from Collins et al (2006) 150
L00000012 G2C Homo sapiens Human Synaptosome Human orthologues of mouse synaptosome adapted from Collins et al (2006) 152
L00000015 G2C Homo sapiens Human NRC Human orthologues of mouse NRC adapted from Collins et al (2006) 186
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000038 G2C Homo sapiens Pocklington H7 Human orthologues of cluster 7 (mouse) from Pocklington et al (2006) 4
L00000049 G2C Homo sapiens TAP-PSD-95-CORE TAP-PSD-95 pull-down core list (ortho) 120
L00000059 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus 748
L00000061 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus (ortho) 984
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
L00000071 G2C Homo sapiens BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list (ortho) 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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