Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins (PubMed:15358775, PubMed:9853749). Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression (Probable). Under basal conditions, cooperates with FYN to stabilize palmitoyltransferase ZDHHC5 at the synaptic membrane through FYN-mediated phosphorylation of ZDHHC5 and its subsequent inhibition of association with endocytic proteins (By similarity). Interacts through its PDZ domains with ANO2 and NETO1 (PubMed:19474308, PubMed:19243221). Interacts with KCNJ4 (By similarity). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C, GRIN2D (By similarity). Interacts with ERBB4 (By similarity). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (By similarity). Interacts with SYNGAP1 (By similarity). Interacts with ASIC3 (By similarity). Interacts with CXADR (By similarity). Interacts with KCND2 (By similarity). Interacts with SEMA4C (PubMed:11134026). Interacts with LRRC4 and LRRC4B (PubMed:16980967). Interacts through its first PDZ domain with GRIK2 and CRIPT (By similarity). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (By similarity). Interacts through its third PDZ domain with NLGN1 and CRIPT, and probably with NLGN2 and NLGN3 (By similarity). Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN, SIPA1L1 and KIF13B (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (By similarity). Interacts with ADR1B (PubMed:15358775). Interacts with ANKS1B and PRR7 (By similarity). May interact with HTR2A (PubMed:14988405). Interacts with ADAM22, KLHL17 and LGI1 (PubMed:20089912) (By similarity). Interacts with FRMPD4 (via C-terminus) (By similarity). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16828986). Interacts (via N-terminal tandem pair of PDZ domains) with GPER1 (via C-terminus tail motif); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner (By similarity). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N-terminal domain) (By similarity). Interacts with SHANK3 (PubMed:24153177). Interacts with KCNJ4 (PubMed:11997254). Interacts with GPR85 (By similarity). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (By similarity). Interacts with ADGRB1 (By similarity). Found in a complex with PRR7 and GRIN1 (By similarity). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (By similarity). Component of the postsynaptic hippocampal AMPA-type glutamate receptor (AMPAR) complex, at least composed of pore forming AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. Interacts (via its first two PDZ domains) with SHISA6 and SHISA7 (via PDZ-binding motif); the interaction is direct (PubMed:26931375, PubMed:29199957). Interacts (via PDZ domain 2) with SEMA4F (via PDZ-binding motif); this interaction may promote translocation of DLG4/SAP90 to the membrane (PubMed:11483650). Interacts with RPH3A and GRIN2A; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with ABR and BCR (By similarity). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (By similarity). Interacts with C9orf72, SMCR8 and RAB39B (PubMed:31651360). Interacts with ZDHHC5 (PubMed:20178993). High levels in postsynaptic density of neurons in the forebrain. Also in presynaptic region of inhibitory synapses formed by cerebellar basket cells on axon hillocks of Purkinje cells. Suppression of neuronal activity induces synaptic accumulation and clustering of DLG4. Highly expressed in CA1 stratum oriens and stratum radiatum hippocampal neurons (PubMed:26931375). Expressed in the outer plexiform layer of the retina of the eye (at protein level) (PubMed:28334377). The PDZ domain 3 mediates interaction with ADR1B. The L27 domain near the N-terminus of isoform 2 is required for HGS/HRS-dependent targeting to postsynaptic density. Palmitoylated. Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses. Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering. Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis. Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering. Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2. Undergoes rapid synaptic palmitoylation/depalmitoylation cycles during neuronal development which slow down in mature neurons. Ubiquitinated by MDM2 in response to NMDA receptor activation, leading to proteasome-mediated degradation of DLG4 which is required for AMPA receptor endocytosis. Mice with a stop codon in the third PDZ domain have impaired spatial learning. NMDA-mediated synaptic plasticity is lost even though receptor levels and localization are unchanged. Long-term potentiation of synaptic transmission is enhanced due to minimal long-term depression. Belongs to the MAGUK family.