Recombinant Human Disks large homolog 4 (DLG4)

Function

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. 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 (By similarity). 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 (PubMed:26334723)

Subcellular Location

Cell membrane (Lipid-anchor); Postsynaptic density; Synapse; Cytoplasm; Cell projection, axon; Cell projection, dendritic spine; Cell projection, dendrite; Presynapse

Disease Association

Intellectual developmental disorder, autosomal dominant 62 (MRD62) : An autosomal dominant form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD62 is characterized by mild to moderately impaired intellectual development. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Brain

Subunit

Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C, GRIN2D (By similarity). Interacts with ASIC3 (By similarity). Interacts with SEMA4C (By similarity). Interacts with CXADR (By similarity). Interacts with KCND2 (By similarity). Interacts with SYNGAP1 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with ERBB4 (PubMed:10725395). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (PubMed:7477295). Interacts through its first PDZ domain with GRIK2, KCNA4 and CRIPT (PubMed:11744724). 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 (PubMed:9278515). Interacts through its guanylate kinase-like domain with KIF13B (PubMed:10859302). Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN and SIPA1L1 (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (PubMed:12151521). Interacts with ADR1B and ANKS1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22 (PubMed:27066583). Interacts with KLHL17 and LGI1 (By similarity). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16630835). 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 (By similarity). Interacts with KCNJ4 (By similarity). Interacts with GPR85 (PubMed:25780553). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (By similarity). Interacts with ADGRB1 (PubMed:23782696). 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 (By similarity). Interacts with RPH3A and GRIN2A; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with ABR and BCR (PubMed:20962234). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (PubMed:21119615). Interacts with C9orf72, SMCR8 and RAB39B (By similarity). Interacts with ZDHHC5 (PubMed:26334723). Interacts with PTEN (via PDZ domain-binding motif); the interaction is induced by NMDA and is required for PTEN location at postsynaptic density (By similarity). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CACNG8 and CNIH2 (By similarity). Interacts with FAM81A; the interaction facilitates condensate formation via liquid-liquid phase separation (By similarity). Interacts with ADGRL3 (By similarity). Interacts with SORCS3 (By similarity). Interacts with ABTB3; the interaction stabilizes DLG4 at glutamatergic synapses (By similarity)

• Stathakis D.G. et al. Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues. — Genomics (1997)
• Stathakis D.G. et al. PubMed: CI-DFSK9A9TB5UR2 (JUL-)
• Stathakis D.G. et al. Genomic organization of human DLG4, the gene encoding postsynaptic density 95. — J. Neurochem. (1999)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Zody M.C. et al. DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage. — Nature (2006)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• Brenman J.E. et al. PubMed: CI-92422QAE4Q70K (AUG-)
• Kim E. et al. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. — Nature (1995)