UniProt functional annotation for P31016



	UniProt functional annotation for P31016

UniProt code: P31016.

Organism: Rattus norvegicus (Rat).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.

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 (PubMed:15317815, PubMed:15358863, PubMed:19596852, PubMed:23300088, PubMed:26679993). 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 (By similarity). 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 (PubMed:19596852). {ECO:0000250|UniProtKB:Q62108, ECO:0000269|PubMed:15317815, ECO:0000269|PubMed:15358863, ECO:0000269|PubMed:19596852, ECO:0000269|PubMed:23300088, ECO:0000269|PubMed:26679993}.

Subunit: Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts with KCNJ4 (PubMed:11997254). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C and GRIN2D (PubMed:7569905). Interacts with ERBB4 (By similarity). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with SYNGAP1 (PubMed:9581761). Interacts with ASIC3 (PubMed:15317815). Interacts with SEMA4C (PubMed:11134026). Interacts with CXADR (PubMed:15304526). Interacts with KCND2 (PubMed:11923279). Interacts (via first PDZ domain) with CRIPT (PubMed:9581762). Interacts through its first PDZ domain with GRIK2 and KCNA4 (By similarity). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (PubMed:23300088). 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 and SIPA1L1 (PubMed:9115257, PubMed:9756850, PubMed:11502259, PubMed:9786987). Interacts through its guanylate kinase-like domain with KIF13B (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (By similarity). Interacts with ANKS1B (PubMed:17334360). Interacts with ADR1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22, KLHL17 and LGI1 (PubMed:16054660, PubMed:16990550, PubMed:20089912). Interacts with FRMPD4 (via C- terminus) (PubMed:19118189). Interacts with LRFN1 and LRFN2 (PubMed:16495444, PubMed:16630835). Interacts with LRFN4 (By similarity). 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 (PubMed:23300088). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N- terminal domain) (PubMed:23300088). Interacts with SHANK3 (By similarity). Interacts with GPR85 (By similarity). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (PubMed:27756895). Interacts with ADGRB1 (By similarity). Found in a complex with PRR7 and GRIN1 (PubMed:27458189). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (PubMed:27458189, PubMed:15629447). 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 (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 (PubMed:26679993). Interacts with ABR and BCR (PubMed:20962234). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (PubMed:21119615). {ECO:0000250|UniProtKB:P78352, ECO:0000250|UniProtKB:Q62108, ECO:0000269|PubMed:11134026, ECO:0000269|PubMed:11483650, ECO:0000269|PubMed:11502259, ECO:0000269|PubMed:11923279, ECO:0000269|PubMed:11997254, ECO:0000269|PubMed:14642282, ECO:0000269|PubMed:15304526, ECO:0000269|PubMed:15317815, ECO:0000269|PubMed:15629447, ECO:0000269|PubMed:16054660, ECO:0000269|PubMed:16495444, ECO:0000269|PubMed:16630835, ECO:0000269|PubMed:16990550, ECO:0000269|PubMed:17334360, ECO:0000269|PubMed:19118189, ECO:0000269|PubMed:20089912, ECO:0000269|PubMed:20962234, ECO:0000269|PubMed:21119615, ECO:0000269|PubMed:23300088, ECO:0000269|PubMed:26679993, ECO:0000269|PubMed:27458189, ECO:0000269|PubMed:27756895, ECO:0000269|PubMed:7569905, ECO:0000269|PubMed:9115257, ECO:0000269|PubMed:9581761, ECO:0000269|PubMed:9581762, ECO:0000269|PubMed:9756850, ECO:0000269|PubMed:9786987}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:10629226, ECO:0000269|PubMed:14642282, ECO:0000269|PubMed:9115257, ECO:0000305|PubMed:11997254}; Lipid-anchor {ECO:0000269|PubMed:10629226}; Cytoplasmic side {ECO:0000269|PubMed:10629226}. Cell junction, synapse, postsynaptic density {ECO:0000269|PubMed:10629226, ECO:0000269|PubMed:11483650, ECO:0000269|PubMed:26679993, ECO:0000269|PubMed:27307232, ECO:0000269|PubMed:27756895, ECO:0000269|PubMed:9115257}. Cell junction, synapse {ECO:0000269|PubMed:11483650, ECO:0000269|PubMed:11502259, ECO:0000269|PubMed:14642282, ECO:0000269|PubMed:19596852, ECO:0000269|PubMed:20089912, ECO:0000269|PubMed:20962234, ECO:0000269|PubMed:27307232, ECO:0000269|PubMed:8922396, ECO:0000269|PubMed:9115257}. Cytoplasm {ECO:0000269|PubMed:9115257}. Cell projection, axon {ECO:0000269|PubMed:20089912, ECO:0000269|PubMed:8922396}. Cell projection, dendritic spine {ECO:0000269|PubMed:10629226, ECO:0000269|PubMed:26679993, ECO:0000269|PubMed:30021165}. Cell projection, dendrite {ECO:0000269|PubMed:10629226, ECO:0000269|PubMed:11483650}. Cell junction, synapse, presynapse {ECO:0000269|PubMed:8922396}. Note=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 (PubMed:19596852). {ECO:0000269|PubMed:19596852, ECO:0000269|PubMed:8922396}.

Tissue specificity: Expressed in brain (at protein level) (PubMed:12151521, PubMed:27307232, PubMed:20962234). Detected in juxtaparanodal zones in the central nervous system and at nerve terminal plexuses of basket cells in the cerebellum (PubMed:20089912). Expressed in cerebrum (PubMed:27307232). Expressed in hippocampal neurons (at protein level) (PubMed:11502259, PubMed:12151521, PubMed:27307232, PubMed:27756895). Isoform 1 and isoform 2: highly expressed in cerebellum, cortex, hippocampus, and corpus striatum (PubMed:12151521, PubMed:20962234). {ECO:0000269|PubMed:11502259, ECO:0000269|PubMed:12151521, ECO:0000269|PubMed:20089912, ECO:0000269|PubMed:20962234, ECO:0000269|PubMed:27307232, ECO:0000269|PubMed:27756895}.

Developmental stage: Expression gradually increases from late embryonic (E18) stage until adulthood. {ECO:0000269|PubMed:20962234}.

Domain: The PDZ domain 3 mediates interaction with ADR1B. {ECO:0000250}.

Domain: The L27 domain near the N-terminus of isoform 2 is required for HGS/HRS-dependent targeting to postsynaptic density. {ECO:0000250}.

Ptm: Palmitoylated (PubMed:10629226, PubMed:27307232). Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses (PubMed:10629226, PubMed:27307232). Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering (PubMed:19596852). Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis (PubMed:15603741, PubMed:31189538). Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering (PubMed:27307232). Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2 (PubMed:27307232). Undergoes rapid synaptic palmitoylation/depalmitoylation cycle during neuronal development which slows down in mature neurons (PubMed:27307232). {ECO:0000269|PubMed:10629226, ECO:0000269|PubMed:15603741, ECO:0000269|PubMed:19596852, ECO:0000269|PubMed:27307232, ECO:0000269|PubMed:31189538}.

Ptm: Ubiquitinated by MDM2 in response to NMDA receptor activation, leading to proteasome-mediated degradation of DLG4 which is required for AMPA receptor endocytosis. {ECO:0000269|PubMed:14642282}.

Similarity: Belongs to the MAGUK family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



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 (PubMed:15317815, PubMed:15358863, PubMed:19596852, PubMed:23300088, PubMed:26679993). 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 (By similarity). 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 (PubMed:19596852). {ECO:0000250\|UniProtKB:Q62108, ECO:0000269\|PubMed:15317815, ECO:0000269\|PubMed:15358863, ECO:0000269\|PubMed:19596852, ECO:0000269\|PubMed:23300088, ECO:0000269\|PubMed:26679993}.


Subunit:		Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts with KCNJ4 (PubMed:11997254). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C and GRIN2D (PubMed:7569905). Interacts with ERBB4 (By similarity). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with SYNGAP1 (PubMed:9581761). Interacts with ASIC3 (PubMed:15317815). Interacts with SEMA4C (PubMed:11134026). Interacts with CXADR (PubMed:15304526). Interacts with KCND2 (PubMed:11923279). Interacts (via first PDZ domain) with CRIPT (PubMed:9581762). Interacts through its first PDZ domain with GRIK2 and KCNA4 (By similarity). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (PubMed:23300088). 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 and SIPA1L1 (PubMed:9115257, PubMed:9756850, PubMed:11502259, PubMed:9786987). Interacts through its guanylate kinase-like domain with KIF13B (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (By similarity). Interacts with ANKS1B (PubMed:17334360). Interacts with ADR1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22, KLHL17 and LGI1 (PubMed:16054660, PubMed:16990550, PubMed:20089912). Interacts with FRMPD4 (via C- terminus) (PubMed:19118189). Interacts with LRFN1 and LRFN2 (PubMed:16495444, PubMed:16630835). Interacts with LRFN4 (By similarity). 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 (PubMed:23300088). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N- terminal domain) (PubMed:23300088). Interacts with SHANK3 (By similarity). Interacts with GPR85 (By similarity). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (PubMed:27756895). Interacts with ADGRB1 (By similarity). Found in a complex with PRR7 and GRIN1 (PubMed:27458189). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (PubMed:27458189, PubMed:15629447). 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 (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 (PubMed:26679993). Interacts with ABR and BCR (PubMed:20962234). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (PubMed:21119615). {ECO:0000250\|UniProtKB:P78352, ECO:0000250\|UniProtKB:Q62108, ECO:0000269\|PubMed:11134026, ECO:0000269\|PubMed:11483650, ECO:0000269\|PubMed:11502259, ECO:0000269\|PubMed:11923279, ECO:0000269\|PubMed:11997254, ECO:0000269\|PubMed:14642282, ECO:0000269\|PubMed:15304526, ECO:0000269\|PubMed:15317815, ECO:0000269\|PubMed:15629447, ECO:0000269\|PubMed:16054660, ECO:0000269\|PubMed:16495444, ECO:0000269\|PubMed:16630835, ECO:0000269\|PubMed:16990550, ECO:0000269\|PubMed:17334360, ECO:0000269\|PubMed:19118189, ECO:0000269\|PubMed:20089912, ECO:0000269\|PubMed:20962234, ECO:0000269\|PubMed:21119615, ECO:0000269\|PubMed:23300088, ECO:0000269\|PubMed:26679993, ECO:0000269\|PubMed:27458189, ECO:0000269\|PubMed:27756895, ECO:0000269\|PubMed:7569905, ECO:0000269\|PubMed:9115257, ECO:0000269\|PubMed:9581761, ECO:0000269\|PubMed:9581762, ECO:0000269\|PubMed:9756850, ECO:0000269\|PubMed:9786987}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:10629226, ECO:0000269\|PubMed:14642282, ECO:0000269\|PubMed:9115257, ECO:0000305\|PubMed:11997254}; Lipid-anchor {ECO:0000269\|PubMed:10629226}; Cytoplasmic side {ECO:0000269\|PubMed:10629226}. Cell junction, synapse, postsynaptic density {ECO:0000269\|PubMed:10629226, ECO:0000269\|PubMed:11483650, ECO:0000269\|PubMed:26679993, ECO:0000269\|PubMed:27307232, ECO:0000269\|PubMed:27756895, ECO:0000269\|PubMed:9115257}. Cell junction, synapse {ECO:0000269\|PubMed:11483650, ECO:0000269\|PubMed:11502259, ECO:0000269\|PubMed:14642282, ECO:0000269\|PubMed:19596852, ECO:0000269\|PubMed:20089912, ECO:0000269\|PubMed:20962234, ECO:0000269\|PubMed:27307232, ECO:0000269\|PubMed:8922396, ECO:0000269\|PubMed:9115257}. Cytoplasm {ECO:0000269\|PubMed:9115257}. Cell projection, axon {ECO:0000269\|PubMed:20089912, ECO:0000269\|PubMed:8922396}. Cell projection, dendritic spine {ECO:0000269\|PubMed:10629226, ECO:0000269\|PubMed:26679993, ECO:0000269\|PubMed:30021165}. Cell projection, dendrite {ECO:0000269\|PubMed:10629226, ECO:0000269\|PubMed:11483650}. Cell junction, synapse, presynapse {ECO:0000269\|PubMed:8922396}. Note=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 (PubMed:19596852). {ECO:0000269\|PubMed:19596852, ECO:0000269\|PubMed:8922396}.
Tissue specificity:		Expressed in brain (at protein level) (PubMed:12151521, PubMed:27307232, PubMed:20962234). Detected in juxtaparanodal zones in the central nervous system and at nerve terminal plexuses of basket cells in the cerebellum (PubMed:20089912). Expressed in cerebrum (PubMed:27307232). Expressed in hippocampal neurons (at protein level) (PubMed:11502259, PubMed:12151521, PubMed:27307232, PubMed:27756895). Isoform 1 and isoform 2: highly expressed in cerebellum, cortex, hippocampus, and corpus striatum (PubMed:12151521, PubMed:20962234). {ECO:0000269\|PubMed:11502259, ECO:0000269\|PubMed:12151521, ECO:0000269\|PubMed:20089912, ECO:0000269\|PubMed:20962234, ECO:0000269\|PubMed:27307232, ECO:0000269\|PubMed:27756895}.
Developmental stage:		Expression gradually increases from late embryonic (E18) stage until adulthood. {ECO:0000269\|PubMed:20962234}.
Domain:		The PDZ domain 3 mediates interaction with ADR1B. {ECO:0000250}.
Domain:		The L27 domain near the N-terminus of isoform 2 is required for HGS/HRS-dependent targeting to postsynaptic density. {ECO:0000250}.
Ptm:		Palmitoylated (PubMed:10629226, PubMed:27307232). Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses (PubMed:10629226, PubMed:27307232). Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering (PubMed:19596852). Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis (PubMed:15603741, PubMed:31189538). Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering (PubMed:27307232). Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2 (PubMed:27307232). Undergoes rapid synaptic palmitoylation/depalmitoylation cycle during neuronal development which slows down in mature neurons (PubMed:27307232). {ECO:0000269\|PubMed:10629226, ECO:0000269\|PubMed:15603741, ECO:0000269\|PubMed:19596852, ECO:0000269\|PubMed:27307232, ECO:0000269\|PubMed:31189538}.
Ptm:		Ubiquitinated by MDM2 in response to NMDA receptor activation, leading to proteasome-mediated degradation of DLG4 which is required for AMPA receptor endocytosis. {ECO:0000269\|PubMed:14642282}.
Similarity:		Belongs to the MAGUK family. {ECO:0000305}.