Affinage

DLG4

Disks large homolog 4 · UniProt P78352

Length
724 aa
Mass
80.5 kDa
Annotated
2026-06-09
100 papers in source corpus 54 papers cited in narrative 54 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DLG4/PSD-95 is a multidomain membrane-associated scaffolding protein that organizes the postsynaptic density (PSD) of excitatory glutamatergic synapses, where it localizes exclusively to postsynaptic sites and is essential for the three-dimensional architecture of the PSD (PMID:8778289, PMID:21525273). Its tandem PDZ domains are functionally specialized: PDZ1/PDZ2 cluster NMDA receptor NR2 subunits, neuroligins, and inwardly rectifying and voltage-gated K+ channels at the surface membrane, while PDZ3 binds distinct partners including neuroligins and CRIPT, the latter linking the scaffold to microtubules (PMID:9278515, PMID:9148889, PMID:9581762, PMID:10629225, PMID:10627592). PSD-95 controls AMPA receptor synaptic content indirectly by binding the auxiliary subunit stargazin through PDZ1/2; this interaction restrains AMPAR lateral diffusion and is required for AMPAR accumulation and retention at synapses (PMID:12359873, PMID:17329211). Through its catalytically inactive guanylate kinase (GK) domain, which binds GMP but lacks enzymatic activity, PSD-95 recruits GKAP/SAPAPs in a phosphorylation-dependent manner—a contact whose structural basis is defined and whose disruption by a GK-domain mutation causes intellectual disability—and thereby nucleates the Shank–Homer–mGluR signaling network (PMID:9024696, PMID:7867790, PMID:29281827, PMID:10433269). PSD-95 additionally scaffolds signaling enzymes, coupling NMDARs to SynGAP and to nNOS, the latter linkage driving excitotoxic vulnerability and multiinnervated spine formation (PMID:9581761, PMID:17855605, PMID:19075115). N-terminal palmitoylation switches PSD-95 from a compact to an extended conformation required for receptor association and membrane anchoring; this modification is written by DHHC palmitoyl-acyltransferases, erased by ABHD17 depalmitoylases through rapid cycling, and competes reciprocally with S-nitrosylation at the same cysteines (PMID:15603741, PMID:27307232, PMID:27956638, PMID:21745643). The scaffold's synaptic abundance and incorporation are dynamically tuned by ubiquitination via Mdm2 (driving proteasomal turnover and AMPAR endocytosis), by phosphorylation (CaMKII at PDZ1-Ser73 releasing NR2A), by Ca2+/calmodulin binding to its N-terminus during homeostatic scaling down, and by anchoring partners α-actinin and ephrin-B3 (PMID:14642282, PMID:17156196, PMID:29118000, PMID:29429936, PMID:26479588). Its expression is gated post-transcriptionally by PTBP1/2-mediated exon 18 repression coupled to nonsense-mediated decay during development and by miR-125a/FMRP translational control at mature synapses (PMID:22246437, PMID:21658607). A PSD-95 GK-domain mutation found in patients establishes a direct link to intellectual disability (PMID:29281827).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 High

    Established that PSD-95 is a dedicated postsynaptic scaffold whose individual PDZ domains are functionally specialized to bind distinct membrane partners, defining the molecular logic of receptor clustering.

    Evidence Co-IP from forebrain with PDZ domain-specific binding assays, plus immunogold EM localization to the PSD

    PMID:8778289 PMID:9148889 PMID:9278515

    Open questions at the time
    • Did not resolve stoichiometry or higher-order organization of the scaffold
    • Functional consequences of clustering in intact synapses not yet tested
  2. 1997 High

    Showed the GK domain is a protein-interaction module rather than an enzyme, recruiting GKAP/SAPAPs and anchoring PSD-95 to the PSD core.

    Evidence GST pulldown, Co-IP from brain, heterologous cell clustering and fractionation; earlier nucleotide-binding/enzymatic assays

    PMID:7867790 PMID:9024696 PMID:9115257 PMID:9756850

    Open questions at the time
    • Phosphorylation requirement of the GKAP/SAPAP interaction not yet known
    • Atomic basis of GK–ligand recognition unresolved at this stage
  3. 1998 High

    Demonstrated that PSD-95 nucleates signaling enzymes and additional ionotropic receptors, linking the NMDAR complex to Ras regulation (SynGAP) and bridging to mGluR/Homer networks.

    Evidence Yeast two-hybrid, Co-IP from brain, in vitro GAP assay, kainate-receptor clustering and electrophysiology

    PMID:10433269 PMID:9581761 PMID:9808460

    Open questions at the time
    • How receptor and enzyme occupancy is coordinated on one scaffold not addressed
    • In vivo significance of SynGAP coupling not yet tested genetically
  4. 1999 High

    Revealed PSD-95 as a kinase-scaffolding platform that promotes Fyn-mediated NR2A tyrosine phosphorylation by co-binding receptor and kinase.

    Evidence Co-IP, heterologous cell phosphorylation assay, domain-mapping, validation in fyn-mutant mice

    PMID:9892651

    Open questions at the time
    • Regulation of kinase recruitment by synaptic activity unresolved
    • Distinct roles of Src/Yes/Lyn versus Fyn not dissected
  5. 2002 High

    Identified the stargazin–PSD-95 PDZ interaction as the essential mechanism by which PSD-95 controls synaptic AMPAR number, and showed PKA phosphorylation of stargazin disrupts this link.

    Evidence Compensatory mutagenesis with slice electrophysiology; phospho-specific antibodies and yeast two-hybrid/Co-IP

    PMID:11805122 PMID:12359873

    Open questions at the time
    • Did not yet show real-time receptor dynamics
    • How phosphorylation is spatially restricted at synapses unknown
  6. 2003 High

    Established that activity-driven ubiquitination of PSD-95 by Mdm2 couples NMDAR signaling to AMPAR endocytosis and LTD, defining a degradative arm of scaffold regulation.

    Evidence Co-IP, ubiquitination assay, proteasome inhibition, AMPAR endocytosis and LTD readouts; later linked to Cdk5 control of Mdm2 binding

    PMID:14642282 PMID:21849563

    Open questions at the time
    • Precise ubiquitinated residues and chain topology not defined
    • How degradation is spatially confined to specific synapses unresolved
  7. 2007 High

    Showed PSD-95 restrains AMPAR–stargazin lateral diffusion to trap receptors at synapses, and that NR2/nNOS preferentially engage PDZ2 to drive excitotoxic and structural plasticity.

    Evidence Single quantum-dot tracking and FRAP in live neurons; quantitative PDZ binding plus siRNA NMDA-toxicity and MIS assays

    PMID:17329211 PMID:17855605 PMID:19075115

    Open questions at the time
    • Mechanistic basis of diffusional trapping at single-molecule resolution incomplete
    • How excitotoxic versus plasticity outputs of nNOS coupling are partitioned unknown
  8. 2011 High

    Defined the architectural and conformational basis of PSD-95 function: vertical filament arrays essential for PSD 3D organization, palmitoylation/S-nitrosylation competition controlling membrane anchoring, and translational gating by miR-125a/FMRP.

    Evidence Electron tomography with RNAi; S-nitrosylation/palmitoylation assays with ZDHHC8 KO; AGO2/FMRP phospho-mutant and miRNA studies

    PMID:19828799 PMID:21525273 PMID:21658607 PMID:21745643

    Open questions at the time
    • The protein partners forming the vertical filaments not fully enumerated
    • Coupling of NO signaling to specific physiological stimuli incomplete
  9. 2016 High

    Resolved palmitoylation as a conformational switch (compact-to-extended) gating receptor binding, identified ABHD17 enzymes as the depalmitoylases enabling rapid cycling, and showed PSD-95 destabilizes the phosphatase STEP61 to enrich synaptic NMDARs.

    Evidence FRET and EM with palmitoylation manipulation; serine-hydrolase screen and APEGS kinetics; Co-IP plus PSD-95 KO mice and electrophysiology

    PMID:27307232 PMID:27457929 PMID:27956638

    Open questions at the time
    • What triggers the conformational switch in vivo not defined
    • Selectivity of individual ABHD17 paralogs at synapses unresolved
  10. 2017 High

    Provided atomic and quantitative mechanism for partner regulation: crystal structure of the GK–phospho-SAPAP complex (explaining an intellectual-disability mutation), and PDZ tyrosine phosphorylation tuning stargazin affinity.

    Evidence Crystallography with binding/synaptogenesis assays; semisynthetic phospho-PDZ domains with NMR and single-molecule FRET

    PMID:28692247 PMID:29281827

    Open questions at the time
    • Kinases responsible for the relevant PDZ tyrosine phosphorylation in neurons not identified
    • Generality of the ID-mutation mechanism across patients untested
  11. 2019 High

    Identified anchoring and transport determinants—α-actinin and ephrin-B3 stabilizing synaptic PSD-95, Ca2+/calmodulin mediating activity-dependent removal during scaling down, and KIF5 driving dendritic delivery.

    Evidence Co-IP and reciprocal mutagenesis with AMPAR imaging; NMR with charge-inversion CaM mutagenesis and mEPSC recording; KIF5A dominant-negative dendritic quantification

    PMID:26479588 PMID:29118000 PMID:29429936 PMID:31753031

    Open questions at the time
    • How anchoring, transport, and turnover are temporally coordinated unresolved
    • Stoichiometry of α-actinin/ephrin-B3 anchoring within the lattice unknown
  12. 2012 High

    Established developmental and disease-relevant control of PSD-95 abundance via PTBP1/2-dependent exon 18 splicing/NMD and downstream roles in dopaminergic, epileptic, and amyloid pathology.

    Evidence RT-PCR/NMD and PTBP knockdown/re-expression; single quantum-dot D1R imaging in dyskinesia models; LGI1/ADAM22 epistasis; Aβ/PP1 rescue experiments

    PMID:22246437 PMID:23041629 PMID:26178195 PMID:34077732

    Open questions at the time
    • Whether splicing control persists in adult plasticity unclear
    • Direct causal contribution of PSD-95 to each disease state varies in strength

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full repertoire of PSD-95 modifications, conformational states, anchoring partners, and degradation pathways are integrated in real time to set synaptic strength remains unresolved.
  • No unified quantitative model linking palmitoylation cycling, phosphorylation, and ubiquitination to receptor content
  • Non-neuronal roles (epithelial polarity, tumor suppression) remain mechanistically isolated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5 GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
ACTN2CACNG2DLGAP1EFNB3GRIN2ANLGN1NOS1SYNGAP1
Complex memberships
NMDAR–MAGUK complexPSD-95/GKAP/SAPAP complexShank–Homer–mGluR complexpostsynaptic density

Evidence

Reading pass · 54 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 PSD-95 binds to the cytoplasmic COOH-termini of neuroligins via its third PDZ domain, while NMDA receptor subunit 2 (NMDA2) and K+ channels interact with the first and second PDZ domains, demonstrating that different PDZ domains are specialized for distinct functions. Co-immunoprecipitation from mouse forebrain; PDZ domain-specific binding assays Science High 9278515
1997 PSD-95 interacts via its guanylate kinase-like (GK) domain with GKAP (guanylate kinase-associated protein), a novel synaptic protein; the GK domain functions as a protein-protein interaction module rather than an enzyme, and PSD-95/GKAP co-cluster with K+ channels/NMDA receptors in heterologous cells. GST pulldown; Co-immunoprecipitation from brain; heterologous cell clustering assay The Journal of cell biology High 9024696
1997 PSD-95 clusters the inwardly rectifying potassium channel Kir4.1 at the cell membrane via direct PDZ-dependent interaction with the Ser-Asn-Val C-terminal motif, and co-expression doubles whole-cell Kir4.1 current amplitude. Co-immunoprecipitation; GST pulldown; electrophysiology in mammalian cells; deletion mutagenesis The Journal of biological chemistry High 9148889
1997 PSD-95 is exclusively associated with the postsynaptic density at forebrain synapses and does not label presynaptic terminals, as established by immunogold electron microscopy of forebrain synaptosomes. Immunogold electron microscopy; subcellular fractionation The Journal of neuroscience High 8778289
1997 SAPAPs (SAP90/PSD-95-Associated Proteins) are a family of proteins that specifically interact with PSD-95/SAP90 through the guanylate kinase domain and recruit PSD-95 to the plasma membrane, suggesting a role in anchoring PSD-95 to the PSD. Yeast two-hybrid; Co-immunoprecipitation; heterologous cell overexpression The Journal of biological chemistry Medium 9115257
1998 SynGAP, a novel Ras-GTPase activating protein, interacts with the PDZ domains of PSD-95 in vitro and in vivo, forms a macromolecular complex with PSD-95 and the NMDA receptor at excitatory synapses, and negatively regulates Ras activity, linking NMDA receptor signaling to Ras pathway modulation. Yeast two-hybrid; Co-immunoprecipitation from brain; in vitro GAP activity assay Neuron High 9581761
1998 SAP90/PSD-95 colocalizes and co-immunoprecipitates with kainate receptor subunits GluR6 and KA2; GluR6 clustering is mediated by its C-terminal ETMA sequence interacting with PDZ1 of SAP90, while KA2 binds the SH3 and GK domains; SAP90 co-expression reduces GluR6/KA2 desensitization. Co-immunoprecipitation; heterologous cell clustering; electrophysiology Neuron High 9808460
1998 CRIPT binds selectively to the third PDZ domain (PDZ3) of PSD-95 via its C-terminus, causes redistribution of PSD-95 to microtubules in heterologous cells, and co-immunoprecipitates with PSD-95 and tubulin from brain, suggesting CRIPT links PSD-95 to the microtubule cytoskeleton. Yeast two-hybrid; Co-immunoprecipitation from brain; heterologous cell redistribution assay Neuron Medium 9581762
1998 BEGAIN, a brain-enriched protein, interacts with the GK domain of PSD-95/SAP90 and is recruited to the Triton X-100-insoluble PSD fraction by SAPAP when co-expressed with PSD-95, identifying BEGAIN as a component of the core PSD-95/SAPAP complex. Yeast two-hybrid; Co-immunoprecipitation; fractionation in transfected cells The Journal of biological chemistry Medium 9756850
1999 PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the NMDA receptor subunit NR2A by scaffolding: different regions of PSD-95 bind NR2A and Fyn simultaneously, enabling complex formation and enhancing phosphorylation. PSD-95 also associates with Src, Yes, and Lyn. Co-immunoprecipitation; heterologous cell phosphorylation assay; domain-mapping Proceedings of the National Academy of Sciences of the United States of America High 9892651
1999 Shank proteins bridge Homer complexes and PSD-95/GKAP complexes at the postsynaptic density: Shank binds Homer via a single Homer-binding site and co-immunoprecipitates from brain; in heterologous cells Shank clusters mGluR5 and mediates coclustering of Homer with PSD-95/GKAP. Co-immunoprecipitation from brain; heterologous cell clustering assay; yeast two-hybrid Neuron High 10433269
1999 Citron, a Rho-effector, interacts with PSD-95/SAP90 both in vivo and in vitro, co-localizes at glutamatergic synapses in thalamic neurons, and can form a heteromeric complex with PSD-95 and NMDA receptors in heterologous cells, linking Rho signaling to the NMDA receptor complex. Co-immunoprecipitation from brain; in vitro binding; heterologous cell co-expression The Journal of neuroscience Medium 9870943
1999 Protein tyrosine phosphatase zeta/RPTPbeta interacts with the second PDZ domain of PSD-95/SAP90 via its C-terminal sequence, as shown by yeast two-hybrid; RPTPbeta concentrates in the postsynaptic density fraction by subcellular fractionation. Yeast two-hybrid; subcellular fractionation; immunohistochemistry Brain research. Molecular brain research Low 10521598
1995 SAP90/PSD-95 binds GMP in the micromolar range but displays no detectable guanylate kinase enzymatic activity, establishing that the GK domain is a nucleotide-binding but catalytically inactive module. Nucleotide binding assay (GMP, ATP, GDP, ADP); enzymatic activity assay FEBS letters Medium 7867790
2000 PSD-95 promotes clustering of voltage-gated Kv channels only when channels are present at the cell surface, acting at the plasma membrane, whereas SAP97 retains Kv channels intracellularly in ER-derived vesicles, demonstrating mechanistically distinct clustering modes. Immunofluorescence; Co-immunoprecipitation; surface expression analysis in heterologous cells The Journal of cell biology Medium 10629225
2000 Kir2.1 and Kir2.3 (but not Kir3 subunits) bind PSD-95 PDZ domains via their C-terminal motif; PSD-95 co-expression suppresses Kir2.3 channel activity by >50%, predominantly affecting single-channel conductance. Yeast two-hybrid; Co-immunoprecipitation; patch-clamp electrophysiology in HEK-293 cells The Journal of neuroscience Medium 10627592
2002 Direct binding of the first two PDZ domains of PSD-95 to stargazin is required to localize AMPA receptors to synapses; increasing PSD-95 at synapses recruits new AMPARs without changing surface AMPAR number, and compensatory mutations in both PSD-95 and stargazin confirm the centrality of this direct interaction. Hippocampal slice cultures; biolistic gene transfection; electrophysiology; compensatory mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 12359873
2002 PKA phosphorylates stargazin at Thr-321, and phosphorylation eliminates the stargazin–PSD-95 PDZ interaction, reducing synaptic AMPAR targeting, as shown by phospho-mimetic mutations abrogating yeast two-hybrid interaction, Co-IP, and co-clustering. Phospho-specific antibodies; PKA phosphorylation assay; yeast two-hybrid; Co-immunoprecipitation; heterologous cell clustering The Journal of biological chemistry High 11805122
2003 PSD-95 is ubiquitinated by the E3 ligase Mdm2; NMDA receptor activation triggers PSD-95 ubiquitination and proteasome-dependent removal from synapses; mutations blocking ubiquitination prevent NMDA-induced AMPAR endocytosis; proteasome inhibitors block NMDA-induced AMPAR internalization and LTD. Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor treatment; AMPAR endocytosis assay Neuron High 14642282
2004 A subset of mammalian DHHC-domain proteins (P-PATs) specifically palmitoylate PSD-95 in vitro and in vivo; inhibition of P-PAT activity in neurons reduces PSD-95 palmitoylation, synaptic clustering, and AMPAR-mediated neurotransmission. In vitro palmitoylation assay; cell-based palmitoylation assay; substrate specificity comparison; neuronal inhibition with functional readout Neuron High 15603741
2004 PSD-95 is phosphorylated by SAPK3/p38gamma at Thr287 and Ser290 (in vitro) and at Ser290 in cells in response to stress; SAPK3 binds preferentially to the third PDZ domain of SAP90, and this binding is required for phosphorylation. ERK1/ERK2 also phosphorylates SAP90 at Thr287 and Ser290 in vitro but independently of PDZ binding. In vitro kinase assay; cell-based phosphorylation; Tat-peptide disruption; Co-immunoprecipitation from synaptic junctions The Biochemical journal Medium 14741046
2004 Neuregulin-1 intracellular domain (Nrg-ICD) translocates to the nucleus upon depolarization, binds the zinc-finger transcription factor Eos, and the Nrg-ICD–Eos complex upregulates PSD-95 transcription via the PSD-95 promoter in a gamma-secretase-independent manner. Reporter gene assay; Co-immunoprecipitation; in vivo promoter activity assay Nature neuroscience Medium 15494726
2004 IRSp53 links postsynaptic Shank1 to PSD-95 by forming a tripartite complex: IRSp53 binds PSD-95 PDZ2 domain via its C-terminal PDZ-binding motif, recruits PSD-95 into filopodia in HEK cells, and the interaction is confirmed by Co-IP from brain. Co-immunoprecipitation from brain; heterologous cell targeting assay; yeast two-hybrid Journal of neurochemistry Medium 15255944
2005 mPins interacts with PSD-95 and SAP102, facilitates formation of the NMDAR–MAGUK complex, and enhances trafficking of SAP102 and NMDARs to the plasma membrane; dominant-negative and siRNA knockdown of mPins reduces SAP102 in dendrites and alters NMDAR surface expression. Co-immunoprecipitation; dominant-negative expression; siRNA knockdown; surface receptor assay in neurons Nature cell biology Medium 16299499
2005 GLYT1 interacts with PDZ domains I and II of PSD-95 via its C-terminal -SRI motif; this interaction stabilizes GLYT1 at the plasma membrane, blocks its internalization, and increases glycine uptake Vmax. Co-immunoprecipitation from rat brain; mutational analysis; glycine uptake assay Journal of neurochemistry Medium 16271045
2006 CaMKII phosphorylates PSD-95 at Ser73 within the PDZ1 domain, causing dissociation of NR2A (but not NR2B) from PSD-95, identified by in vitro kinase assay, point mutagenesis, phospho-specific antibody, and validated in hippocampal neurons. In vitro kinase assay with GST-PSD-95; point mutagenesis; phospho-specific antibody; transfected COS-7 and cultured neurons The European journal of neuroscience High 17156196
2006 PSD-95 and PKC potentiate NMDAR gating and surface expression in a non-additive manner; PSD-95 partially occludes PKC potentiation; Ser-1462 in the PDZ-binding motif of NR2A is required for PSD-95-induced potentiation. Xenopus oocyte electrophysiology; immunofluorescence; Co-immunoprecipitation; mutagenesis Proceedings of the National Academy of Sciences of the United States of America Medium 17179037
2006 PSD-95 interacts with Src via a 12-amino-acid N-terminal sequence that binds the Src SH2 domain in a phosphotyrosine-independent manner, inhibits Src kinase activity, reduces NMDAR phosphorylation, depresses NMDAR currents, and inhibits LTP induction. Co-immunoprecipitation; in vitro binding; peptide inhibition; electrophysiology in cultured neurons and hippocampal slices The EMBO journal High 16990796
2007 AMPAR–Stargazin complexes diffuse laterally between extrasynaptic and synaptic sites as a unit; disruption of Stargazin–PSD-95 interaction strongly increases AMPAR surface diffusion and prevents AMPAR accumulation at postsynaptic sites, as measured by single quantum dot tracking and FRAP in live neurons. Single quantum dot tracking; FRAP; live hippocampal neuron imaging Neuron High 17329211
2007 NR2A–NR2C NMDA receptor subunits and nNOS preferentially interact with PSD-95 PDZ2 domain (EC50 ~1 µM for NR2 subunits; ~200 nM for nNOS/PSD-95 interaction by nNOS peptide); knockdown of only PSD-95 or nNOS (not PSD-93, SAP97, SAP102, TIP1) reduces neuronal excitotoxic vulnerability. Proteomic PDZ interaction screen; biochemical binding assays; siRNA knockdown; NMDA toxicity assay in cortical neurons The Journal of neuroscience High 17855605
2008 PSD-95 overexpression promotes multiinnervated spine (MIS) formation through nitric oxide synthase (NOS): deletion of PSD-95 PDZ2 (which interacts with nNOS) prevents MIS formation; siRNA knockdown or pharmacological blockade of NOS also prevents axon varicosity formation and MIS formation, whereas NO donor or cGMP analogue induces MIS. Electron microscopy; genetic deletion of PDZ domains; siRNA; pharmacology; hippocampal slice culture The Journal of cell biology High 19075115
2009 Distinct domains of PSD-95 govern different aspects of its synaptic behavior: N-terminal palmitoylation plus PDZ1/2 interactions stabilize PSD-95 within the PSD; PDZ1/2 interactions also mediate NMDA-receptor-dependent rapid destabilization of PSD-95 during chemical LTD; SH3 domain is additionally needed for a stable PSD-95 lattice. PAGFP photoactivation; two-photon microscopy; PSD-95 domain mutants; rat CA1 pyramidal neurons The Journal of neuroscience High 19828799
2011 PSD-95 is arranged as vertical filaments in regular arrays within the PSD; RNAi knockdown of PSD-95 causes loss of entire patches of PSD material including vertical filaments, horizontal elements, and putative AMPA receptor structures (but not NMDA receptor structures), establishing that PSD-95-containing filaments are essential for 3D PSD organization. Electron tomography; RNAi knockdown; rat hippocampal spine synapse analysis The Journal of neuroscience High 21525273
2011 miR-125a targeting of PSD-95 mRNA reversibly inhibits PSD-95 translation; FMRP phosphorylation promotes formation of an AGO2–miR-125a inhibitory complex on PSD-95 mRNA, while mGluR signaling requires FMRP dephosphorylation and AGO2 release to de-repress translation. miRNA inhibition; FMRP phospho-mutant analysis; Co-IP of AGO2 with PSD-95 mRNA; dendritic spine morphology analysis Molecular cell Medium 21658607
2011 PSD-95 is S-nitrosylated at cysteines 3 and 5, which are the same residues palmitoylated; physiological NO inhibits PSD-95 palmitoylation, reduces synaptic PSD-95 clusters; decreased palmitoylation (via 2-bromopalmitate or ZDHHC8 KO) increases PSD-95 nitrosylation, establishing reciprocal competition between S-nitrosylation and palmitoylation at these cysteines. S-nitrosylation assay; palmitoylation assay; ZDHHC8 knockout mice; granule cell imaging; Co-IP Neuron High 21745643
2011 Cyclin-dependent kinase 5 (Cdk5) regulates PSD-95 ubiquitination: genetic or pharmacological reduction of Cdk5 activity increases Mdm2–PSD-95 interaction and PSD-95 ubiquitination, correlating with increased β-adaptin binding (AP-2 subunit), suggesting a mechanism linking PSD-95 ubiquitination to NMDA-induced AMPAR endocytosis. Co-immunoprecipitation; pharmacological Cdk5 inhibition; genetic Cdk5 reduction (mouse); ubiquitination assay; mass spectrometry The Journal of neuroscience Medium 21849563
2012 PTBP1 and PTBP2 repress PSD-95 exon 18 splicing, leading to premature translation termination and NMD, preventing PSD-95 expression during early neural development; sequential loss of PTBP1 then PTBP2 allows exon 18 inclusion and PSD-95 expression; re-expression of either PTBP in differentiated neurons impairs glutamatergic synapse development. RT-PCR; NMD analysis; PTBP knockdown/re-expression in neurons; synapse development assay Nature neuroscience High 22246437
2012 PSD-95 regulates dopamine D1 receptor (D1R) trafficking and localization in the striatum: disrupting D1R–PSD-95 interaction destabilizes D1R at synapses via increased lateral diffusion, internalization, and diminished surface expression, reducing L-DOPA-induced dyskinesia in rat and macaque models. Single quantum dot imaging; biochemical interaction assay; peptide disruption in vivo; rat/macaque dyskinesia models The Journal of clinical investigation High 23041629
2015 LGI1 acts as a paracrine signal through ADAM22 (via PDZ domain interactions) to set postsynaptic strength; in the absence of LGI1, PSD-95 (but not SAP102) is unable to modulate synaptic transmission, establishing LGI1–ADAM22 as an essential complex regulating the functional incorporation of PSD-95 at mature synapses. Hippocampal slice electrophysiology; viral knockdown; epistasis analysis in LGI1 KO and ADAM22 mutant mice Proceedings of the National Academy of Sciences of the United States of America Medium 26178195
2015 Ephrin-B3 directly interacts with and stabilizes PSD-95 at synapses; activity-dependent MAPK phosphorylation of ephrin-B3 at Ser332 disperses it from synapses, preventing interaction with PSD-95 and increasing PSD-95 turnover, linking neuronal activity to PSD-95 synaptic stability. Super-resolution imaging; biochemical interaction assays; in vivo models; phospho-mutant analysis Nature neuroscience High 26479588
2016 ABHD17A, 17B, and 17C are the physiological PSD-95 depalmitoylating enzymes: they show the strongest depalmitoylating activity toward PSD-95, localize to recycling endosomes and the synaptic fraction, and their inhibition delays PSD-95 depalmitoylation kinetics; most PSD-95 undergoes rapid palmitoylation cycling in neurons, with cycling decelerating during synapse maturation. Serine hydrolase screen; APEGS (acyl-PEGyl exchange gel shift) assay; shRNA knockdown; neuronal palmitoylation kinetics The Journal of neuroscience High 27307232
2016 PSD-95 palmitoylation changes its conformation from compact to extended, and only palmitoylated/extended PSD-95 associates with AMPARs (via TARPs) or NMDARs (via GluN2B); within the PSD, PSD-95 orients perpendicular to the membrane with its palmitoylated N-terminus at the membrane, and changing palmitoylation alters AMPAR but not NMDAR levels. FRET; electron microscopy; subcellular fractionation; palmitoylation manipulation Proceedings of the National Academy of Sciences of the United States of America High 27956638
2016 PSD-95 expression destabilizes STEP61 via ubiquitination and proteasomal degradation, excluding STEP61 from the PSD; STEP61 knockdown increases extrasynaptic (but not synaptic) NMDAR expression; PSD-95 binds STEP61 directly but STEP61 is increased in the PSD of PSD-95 KO mice. Co-immunoprecipitation; subcellular fractionation; PSD-95 KO mice; siRNA knockdown; electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 27457929
2017 TAOK2 directly phosphorylates Septin7 at an evolutionarily conserved residue; this phosphorylation induces Septin7 translocation to dendritic spines where it associates with and stabilizes PSD-95, promoting spine maturation; TAOK2 depletion causes unstable dendritic protrusions and loss of NMDAR calcium compartmentalization. Chemical genetics; mass spectrometry phosphorylation identification; Co-IP; live imaging of spine dynamics; siRNA Neuron Medium 28065648
2017 Phosphorylation of PSD-95 PDZ domains exerts complex effects on binding partners: phosphorylation at Y397 significantly increases affinity for stargazin (confirmed by NMR and single-molecule FRET); phosphomimetic mutations are ineffective substitutes for tyrosine phosphorylation. Semisynthetic phosphorylated PDZ domains; fluorescence anisotropy; NMR; single-molecule FRET ACS chemical biology High 28692247
2017 PSD-95/SAPAP interaction requires phosphorylation of N-terminal repeat sequences of SAPAPs; crystal structure of PSD-95 GK domain in complex with phospho-SAPAP peptide reveals the molecular basis; a PSD-95 GK mutation found in intellectual disability patients disrupts this interaction. Crystal structure; biochemical binding assays; functional synaptogenesis assay; phosphomimetic and mutagenesis analysis Cell reports High 29281827
2017 Ca2+/calmodulin binds to the N-terminus of PSD-95, with E17 interacting with R126 on CaM as identified by NMR; this interaction mediates postsynaptic loss of PSD-95 and AMPARs during homeostatic synaptic scaling down; E17R mutation prevents scaling down, rescued by charge-inversion CaM(R126E). NMR structural analysis; compensatory charge-inversion mutagenesis; miniature EPSC recording in hippocampal neurons The EMBO journal High 29118000
2018 α-Actinin binds to the very N-terminus of PSD-95 (involving K10/K11 of PSD-95 and E53, E213/D217 of α-actinin); knockdown of α-actinin phenocopies PSD-95 knockdown; mutations impairing the interaction reduce postsynaptic localization of both PSD-95 and AMPARs in parallel. Co-immunoprecipitation; mutagenesis; shRNA knockdown; AMPAR localization imaging in neurons Neuron High 29429936
2019 PKA phosphorylates NLGN1 at S839 near the PDZ ligand, reducing PSD-95 binding; impaired NLGN1/PSD-95 binding decreases NLGN1 surface expression and reduces NLGN1-mediated synaptic enhancement. Co-immunoprecipitation; phosphomimetic mutagenesis; surface expression assay; synaptic electrophysiology Proceedings of the National Academy of Sciences of the United States of America Medium 31138690
2019 KIF5 (kinesin) transports PSD-95 to dendrites via interaction between the C-terminal tail of KIF5A and the third PDZ domain of PSD-95; expression of motor-domain-deleted KIF5A reduces dendritic PSD-95 levels; Staufen regulates the KIF5A–PSD-95 association. Co-immunoprecipitation in vitro and in vivo; dominant-negative KIF5A expression; dendritic PSD-95 quantification Molecular brain Medium 31753031
2021 Increased PSD-95 blocks Aβ-induced modification of the NMDAR C-terminal domain conformation and its interaction with PP1, preventing synaptic weakening; pharmacological inhibition of PSD-95 depalmitoylation increases synaptic PSD-95 and rescues Aβ-induced deficits. Electrophysiology; NMDAR CTD conformation assay; Co-IP of NMDAR with PP1; pharmacological depalmitoylation inhibition Cell reports Medium 34077732
2001 DLG4/PSD-95 interacts with the Cyt1 (but not Cyt2) cytoplasmic domain of CD46, and this interaction is required for polarized expression of CD46 in human epithelial cells, demonstrating a non-neuronal role for DLG4 in epithelial polarity. Yeast two-hybrid; Co-immunoprecipitation; dominant-negative DLG4 expression; polarized epithelial cell assay The Journal of biological chemistry Medium 11714708
2006 HPV18 E6 protein targets DLG4/PSD-95 for E6AP-dependent proteasomal degradation via the E6 C-terminal PDZ-binding motif; DLG4 expression suppresses tumorigenicity of CaSki cells without affecting growth in culture, suggesting a tumor suppressor function. E6AP shRNA rescue; in vitro binding/degradation assay; tumorigenicity assay Journal of virology Medium 17121805
2001 GRK5 (but not GRK2) reduces β1-adrenergic receptor (β1AR) association with PSD-95 in a kinase-activity-dependent manner through phosphorylation of β1AR, and agonist stimulation further decreases PSD-95 binding to β1AR. Co-immunoprecipitation; kinase-dead GRK5 mutant; agonist treatment in COS-7 cells The Journal of biological chemistry Medium 11700307

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 879 10433269
2002 Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proceedings of the National Academy of Sciences of the United States of America 614 12359873
1997 Binding of neuroligins to PSD-95. Science (New York, N.Y.) 610 9278515
1998 SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 542 9581761
2007 The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 459 17329211
2003 Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 458 14642282
2004 Identification of PSD-95 palmitoylating enzymes. Neuron 452 15603741
1997 GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. The Journal of cell biology 445 9024696
2007 PSD-95 is required for activity-driven synapse stabilization. Proceedings of the National Academy of Sciences of the United States of America 386 17360496
1999 PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proceedings of the National Academy of Sciences of the United States of America 333 9892651
1997 SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density. The Journal of biological chemistry 314 9115257
2004 Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 312 14980210
2011 Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Molecular cell 311 21658607
1998 CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90. Neuron 264 9581762
1996 PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 258 8778289
2003 PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. The Journal of physiology 257 12563010
2011 PSD-95 is required to sustain the molecular organization of the postsynaptic density. The Journal of neuroscience : the official journal of the Society for Neuroscience 250 21525273
1998 SAP90 binds and clusters kainate receptors causing incomplete desensitization. Neuron 211 9808460
2014 Role of the DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 in schizophrenia. PloS one 206 24416398
2012 PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nature neuroscience 206 22246437
2016 Identification of PSD-95 Depalmitoylating Enzymes. The Journal of neuroscience : the official journal of the Society for Neuroscience 193 27307232
2010 Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. The American journal of psychiatry 181 20952458
2007 PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. The Journal of neuroscience : the official journal of the Society for Neuroscience 179 17855605
2011 Regulation of AMPA receptor surface diffusion by PSD-95 slots. Current opinion in neurobiology 177 22051694
2014 The relationship between PSD-95 clustering and spine stability in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 24501349
2000 PSD-95 and SAP97 exhibit distinct mechanisms for regulating K(+) channel surface expression and clustering. The Journal of cell biology 157 10629225
2017 Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer's disease mice. Brain : a journal of neurology 151 29155979
2000 Improved immunohistochemical detection of postsynaptically located PSD-95/SAP90 protein family by protease section pretreatment: a study in the adult mouse brain. The Journal of comparative neurology 151 11027400
2008 PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling. The Journal of cell biology 144 19075115
2004 Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Nature neuroscience 135 15494726
2011 S-nitrosylation and S-palmitoylation reciprocally regulate synaptic targeting of PSD-95. Neuron 134 21745643
2008 Opposing effects of PSD-93 and PSD-95 on long-term potentiation and spike timing-dependent plasticity. The Journal of physiology 133 18936077
2021 PSD-95 protects synapses from β-amyloid. Cell reports 119 34077732
2008 Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. The international journal of neuropsychopharmacology 116 18570704
2017 TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation. Neuron 113 28065648
2011 PSD-95 and PSD-93 play critical but distinct roles in synaptic scaling up and down. The Journal of neuroscience : the official journal of the Society for Neuroscience 111 21543610
1997 Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90. The Journal of biological chemistry 110 9148889
2014 A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing research reviews 108 25264360
2012 PSD-95 expression controls L-DOPA dyskinesia through dopamine D1 receptor trafficking. The Journal of clinical investigation 108 23041629
2009 Distinct domains within PSD-95 mediate synaptic incorporation, stabilization, and activity-dependent trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience 107 19828799
2002 Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95. The Journal of biological chemistry 106 11805122
2016 PSD-95 stabilizes NMDA receptors by inducing the degradation of STEP61. Proceedings of the National Academy of Sciences of the United States of America 103 27457929
2019 PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment. Scientific reports 102 31263190
2009 PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 102 19494135
2000 Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family. The Journal of neuroscience : the official journal of the Society for Neuroscience 100 10627592
2006 PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating. Proceedings of the National Academy of Sciences of the United States of America 99 17179037
2005 mPins modulates PSD-95 and SAP102 trafficking and influences NMDA receptor surface expression. Nature cell biology 99 16299499
2015 The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function. Proceedings of the National Academy of Sciences of the United States of America 82 26178195
2004 Differential mRNA expression and protein localization of the SAP90/PSD-95-associated proteins (SAPAPs) in the nervous system of the mouse. The Journal of comparative neurology 82 15024750
2003 Interactions between Src family protein tyrosine kinases and PSD-95. Neuropharmacology 82 14529711
1999 Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 9870943
2011 Perturbing PSD-95 interactions with NR2B-subtype receptors attenuates spinal nociceptive plasticity and neuropathic pain. Molecular therapy : the journal of the American Society of Gene Therapy 79 21427709
2004 Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2. The Biochemical journal 79 14741046
1999 Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites. The Journal of biological chemistry 79 10026200
2017 Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infants. Nature communications 78 28874660
2016 Palmitoylation regulates glutamate receptor distributions in postsynaptic densities through control of PSD95 conformation and orientation. Proceedings of the National Academy of Sciences of the United States of America 77 27956638
2013 PSD-95 promotes the stabilization of young synaptic contacts. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 73 24298137
2008 Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction. Neurobiology of disease 73 18424056
2022 Neurodevelopmental Disorders Associated with PSD-95 and Its Interaction Partners. International journal of molecular sciences 72 35457207
2004 A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis. Neuropharmacology 72 15458847
1998 BEGAIN (brain-enriched guanylate kinase-associated protein), a novel neuronal PSD-95/SAP90-binding protein. The Journal of biological chemistry 72 9756850
2016 Posttranslational Modifications Regulate the Postsynaptic Localization of PSD-95. Molecular neurobiology 71 26884267
2006 Calcium-calmodulin-dependent protein kinase II phosphorylation modulates PSD-95 binding to NMDA receptors. The European journal of neuroscience 71 17156196
2004 Synaptic targeting of neuroligin is independent of neurexin and SAP90/PSD95 binding. Molecular and cellular neurosciences 68 15519238
1995 Nucleotide binding by the synapse associated protein SAP90. FEBS letters 67 7867790
2004 Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD-95. Journal of neurochemistry 66 15255944
2014 Durable fear memories require PSD-95. Molecular psychiatry 64 25510511
2001 Knockdown of PSD-95/SAP90 delays the development of neuropathic pain in rats. Neuroreport 64 11711866
2000 Expression of PSD-95/SAP90 is critical for N-methyl-D-aspartate receptor-mediated thermal hyperalgesia in the spinal cord. Neuroscience 64 10854750
2018 α-Actinin Anchors PSD-95 at Postsynaptic Sites. Neuron 63 29429936
2015 Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis. Cell death and differentiation 63 25678324
2011 TrkB and protein kinase Mζ regulate synaptic localization of PSD-95 in developing cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 63 21849550
2001 Molecular mechanisms regulating the differential association of kainate receptor subunits with SAP90/PSD-95 and SAP97. The Journal of biological chemistry 63 11279111
2021 PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides. International journal of molecular sciences 60 34830481
2006 E6AP-dependent degradation of DLG4/PSD95 by high-risk human papillomavirus type 18 E6 protein. Journal of virology 60 17121805
2015 Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3. Nature neuroscience 59 26479588
2013 Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons. Molecular and cellular neurosciences 59 23932971
2000 Three isoforms of synaptic scaffolding molecule and their characterization. Multimerization between the isoforms and their interaction with N-methyl-D-aspartate receptors and SAP90/PSD-95-associated protein. The Journal of biological chemistry 59 10644767
2017 Synaptic Targeting and Function of SAPAPs Mediated by Phosphorylation-Dependent Binding to PSD-95 MAGUKs. Cell reports 58 29281827
2011 Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 55 21849563
2001 A functional interaction between CD46 and DLG4: a role for DLG4 in epithelial polarization. The Journal of biological chemistry 55 11714708
2006 PSD-95 is a negative regulator of the tyrosine kinase Src in the NMDA receptor complex. The EMBO journal 54 16990796
2019 PSD-95 binding dynamically regulates NLGN1 trafficking and function. Proceedings of the National Academy of Sciences of the United States of America 52 31138690
2014 G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility. RNA (New York, N.Y.) 50 25406362
2019 Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions. Molecular brain 48 31753031
1997 Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues. Genomics 46 9286702
2013 A broadly applicable high-throughput screening strategy identifies new regulators of Dlg4 (Psd-95) alternative splicing. Genome research 45 23636947
2005 The scaffolding protein PSD-95 interacts with the glycine transporter GLYT1 and impairs its internalization. Journal of neurochemistry 44 16271045
1999 Protein tyrosine phosphatase zeta/RPTPbeta interacts with PSD-95/SAP90 family. Brain research. Molecular brain research 44 10521598
2021 DLG4-related synaptopathy: a new rare brain disorder. Genetics in medicine : official journal of the American College of Medical Genetics 43 33597769
2016 D-Serine and Serine Racemase Are Associated with PSD-95 and Glutamatergic Synapse Stability. Frontiers in cellular neuroscience 42 26941605
2005 Interaction between SAP97 and PSD-95, two Maguk proteins involved in synaptic trafficking of AMPA receptors. The Journal of biological chemistry 42 16332687
2001 G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95. The Journal of biological chemistry 41 11700307
2001 The PDZ1 domain of SAP90. Characterization of structure and binding. The Journal of biological chemistry 40 11744724
1999 Distinct spatiotemporal expression of mRNAs for the PSD-95/SAP90 protein family in the mouse brain. Neuroscience research 40 10211776
2014 Epigenetic upregulation of PSD-95 contributes to the rewarding behavior by morphine conditioning. European journal of pharmacology 38 24704371
2017 Site-Specific Phosphorylation of PSD-95 PDZ Domains Reveals Fine-Tuned Regulation of Protein-Protein Interactions. ACS chemical biology 37 28692247
2006 Structural modeling of protein interactions by analogy: application to PSD-95. PLoS computational biology 36 17096593
2017 Ca2+/calmodulin binding to PSD-95 mediates homeostatic synaptic scaling down. The EMBO journal 35 29118000
2013 Bidirectional control of postsynaptic density-95 (PSD-95) clustering by Huntingtin. The Journal of biological chemistry 35 24347167

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