DLG4
Encyclopedia
PSD-95 also known as SAP-90 (synapse-associated protein 90) is a protein
that in humans is encoded by the DLG4 (disks large homolog 4) gene
.
PSD-95 is a member of the membrane-associated guanylate kinase
(MAGUK) family. With PSD-93 it is recruited into the same NMDA receptor
and potassium channel
clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.
PSD-95 is the best studied member of the MAGUK-family of PDZ domain
-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain
, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neuron
s, and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin
, NMDA receptor
s, AMPA receptor
s, and potassium channel
s.
, SAP97
and SAP102
. The MAGUKs are defined by their inclusion of PDZ
, SH3
and GUK
domains, although many of them also contain regions homologous of CaMKII
, WW
and L27
domains. The GUK domain that they have is structurally very similar to that of the guanylate kinase
s, however it is known to be catalytically inactive as the P-Loop which binds ATP
is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction.
The PDZ domain
which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at the C-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form a intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and a calmodulin
binding region located elsewhere in the gene.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the DLG4 (disks large homolog 4) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
PSD-95 is a member of the membrane-associated guanylate kinase
Membrane-associated guanylate kinase
The membrane-associated guanylate kinases are a superfamily of proteins. The MAGUKs are defined by their inclusion of PDZ, SH3 and GUK domains, although many of them also contain regions homologous of CaMKII, WW and L27 domains...
(MAGUK) family. With PSD-93 it is recruited into the same NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
and potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.
PSD-95 is the best studied member of the MAGUK-family of PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin
Neuroligin
300px|thumb|right|alt = Colored dice with checkered background|Tertiary structure of Neuroligin 4.Neuroligin , a type I membrane protein, is a protein on the postsynaptic membrane that mediates synapse formation between neurons. Neuroligins mediate signaling across the synapse and affect the...
, NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
s, and potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
s.
MAGUK superfamily and constituent domains
PSD-95 (encoded by DLG4) is a member of the MAGUK superfamily, and part of a subfamily which also includes PSD-93DLG2
Disks large homolog 2 also known as channel-associated protein of synapse-110 or postsynaptic density protein 93 is a protein that in humans is encoded by the DLG2 gene.- Function :...
, SAP97
DLG1
Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene....
and SAP102
DLG3
Disks large homolog 3 also known as neuroendocrine-DLG or synapse-associated protein 102 is a protein that in humans is encoded by the DLG3 gene...
. The MAGUKs are defined by their inclusion of PDZ
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
, SH3
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
and GUK
Guanylate kinase
In enzymology, a guanylate kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and GMP, whereas its two products are ADP and GDP....
domains, although many of them also contain regions homologous of CaMKII
Ca2+/calmodulin-dependent protein kinase
/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the /calmodulin complex...
, WW
WW domain
The WW domain is a protein domain with two highly conserved tryptophans that binds proline-rich peptide motifs...
and L27
L27 domain
The L27 domain is a protein domain that is found in receptor targeting proteins Lin-2 and Lin-7 , as well as some protein kinases and human MPP2 protein.- References :...
domains. The GUK domain that they have is structurally very similar to that of the guanylate kinase
Guanylate kinase
In enzymology, a guanylate kinase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are ATP and GMP, whereas its two products are ADP and GDP....
s, however it is known to be catalytically inactive as the P-Loop which binds ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
is absent. It is thought that the MAGUKs have subfunctionalized the GUK domain for their own purposes, primarily based on its ability to form protein-protein interactions with cytoskeleton proteins, microtubule/actin based machinery and molecules involved in signal transduction.
The PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
which are contained in the MAGUKs in varying numbers, is replicated three times over in PSD-95. PDZ domains are short peptide binding sequences commonly found at the C-terminus of interacting proteins. The three copies within the gene have different binding partners, due to amino acid substitutions within the PSD-95 protein and its ligands. The SH3 domain is again a protein-protein interaction domain. Its family generally bind to PXXP sites, but in MAGUKs it is known to bind to other sites as well. One of the most well known features is that it can form a intramolecular bond with the GUK domain, creating what is known as a GUK-SH3 'closed' state. The regulatory mechanisms and function are unknown but it is hypothesized that it may involve a hook region and a calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
binding region located elsewhere in the gene.
Interactions
PSD-95 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- ADAM22ADAM22Disintegrin and metalloproteinase domain-containing protein 22 also known as ADAM22 is an enzyme that in humans is encoded by the ADAM22 gene.- Function :...
- Beta-1 adrenergic receptorBeta-1 adrenergic receptorThe beta-1 adrenergic receptor , also known as ADRB1, is a beta-adrenergic receptor, and also denotes the human gene encoding it...
- CACNG2CACNG2Calcium channel, voltage-dependent, gamma subunit 2, also known as CACNG2 or stargazin is a protein that in humans is encoded by the CACNG2 gene.-Function:...
- CASKCASKPeripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2 , calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2.-Genomics:This gene is located on the short arm of...
- DLG3DLG3Disks large homolog 3 also known as neuroendocrine-DLG or synapse-associated protein 102 is a protein that in humans is encoded by the DLG3 gene...
- DLGAP1DLGAP1Disks large-associated protein 1 , also known as guanylate kinase-associated protein is a protein that in humans is encoded by the DLGAP1 gene. DAP-1 is known to be highly enriched in synaptosomal preparations of the brain, and present in the post synaptic density This gene encodes the protein...
- DLGAP2DLGAP2Disks large-associated protein 2 is a protein that in humans is encoded by the DLGAP2 gene.-Interactions:DLGAP2 has been shown to interact with DLG4, the canonical synapse marker protein, which in turn binds to N-methyld-aspartate receptors and Shaker-type K+ channels.-Associations:As with many...
- DYNLL1DYNLL1Dynein light chain 1, cytoplasmic is a protein that in humans is encoded by the DYNLL1 gene.-Interactions:DYNLL1 has been shown to interact with DLGAP1, MYO5A, DYNC1I1, BCL2L11, NRF1, IκBα, PAK1, DLG4 and TP53BP1.-Further reading:...
- DYNLL2DYNLL2Dynein light chain 2, cytoplasmic is a protein that in humans is encoded by the DYNLL2 gene.-Interactions:DYNLL2 has been shown to interact with DLG4, DLGAP1, MYO5A and BMF.-Further reading:...
- ERBB4ERBB4Receptor tyrosine-protein kinase erbB-4 is an enzyme that in humans is encoded by the ERBB4 gene. Alternatively spliced variants that encode different protein isoforms have been described; however, not all variants have been fully characterized....
- EXOC4EXOC4Exocyst complex component 4 is a protein that in humans is encoded by the EXOC4 gene.-Interactions:EXOC4 has been shown to interact with DLG4, EXOC7, GRIN2B, EXOC3 and DLG3.-Further reading:...
- FYNFYNProto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
- FZD7FZD7Frizzled-7 is a protein that in humans is encoded by the FZD7 gene.-Further reading:...
- GRIK1GRIK1Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.- Function :...
- GRIK2GRIK2Glutamate receptor, ionotropic kainate 2 is a protein that in humans is encoded by the GRIK2 gene.- Clinical significance :Homozygosity for a GRIK2 deletion-inversion mutation is associated with nonsyndromic autosomal recessive mental retardation....
- GRIK5GRIK5Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the GRIK5 gene.-Interactions:GRIK5 has been shown to interact with DLG4 and GRIK2....
- GRIN2AGRIN2AGlutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.-Interactions:GRIN2A has been shown to interact with FYN, DLG4, DLG3, DLG1, Src, PTK2B and Interleukin 16.-Further reading:...
- GRIN2BGRIN2BGlutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
- GRIN2CGRIN2CGlutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.-Interactions:GRIN2C has been shown to interact with DLG4 and DLG3....
- HER2/neuHER2/neuHER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
- HGSHGS (gene)Hepatocyte growth factor-regulated tyrosine kinase substrate is an enzyme that in humans is encoded by the HGS gene.-Interactions:HGS has been shown to interact with TSG101, STAM2, Merlin, DLG4, IL2RB, EPS15, CLTC and Signal transducing adaptor molecule.-Further reading:...
- KCNA2KCNA2Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the KCNA2 gene.-Interactions:KCNA2 has been shown to interact with KCNA4, DLG4, PTPRA, KCNAB2, RHOA and Cortactin....
- KCNA4KCNA4Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current , the main contributing current to the repolarizing phase 1 of the cardiac action...
- KCNA5KCNA5Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.-Function:...
- KCNJ12KCNJ12ATP-sensitive inward rectifier potassium channel 12 is a protein that in humans is encoded by the KCNJ12 gene.-Interactions:KCNJ12 has been shown to interact with LIN7C, DLG4, LIN7B, DLG2, DLG3, DLG1, APBA1, LIN7A and CASK.- External links :...
- Kir2.1
- LGI1LGI1Leucine-rich, glioma inactivated 1, also known as LGI1, is a protein which in humans is encoded by the LGI1 gene. It may be a metastasis suppressor.-Function:...
- LRP1LRP1Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
- LRP2LRP2Low density lipoprotein-related protein 2 also known as LRP2 or megalin is a protein which in humans is encoded by the LRP2 gene.-Function:...
- NLGN1NLGN1Neuroligin-1 is a protein that in humans is encoded by the NLGN1 gene.-Interactions:NLGN1 has been shown to interact with NRXN1 and DLG4.-Further reading:...
- NOS1NOS1Nitric oxide synthase 1 , also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.- Function :Nitric oxide is a messenger molecule with diverse functions throughout the body...
- PTK2BPTK2BProtein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the PTK2B gene.-Protein:-Interactions:PTK2B has been shown to interact with PTPN11, PTPN6, PITPNM1, Gelsolin, Src, GRIN2A, Ewing sarcoma breakpoint region 1, RB1CC1, TGFB1I1, NPHP1, BCAR1, FYN, DLG4, DLG3, DDEF2, Cbl gene, RAS...
- SEMA4CSEMA4CSemaphorin-4C is a protein that in humans is encoded by the SEMA4C gene.-Further reading:...
and - SHANK2SHANK2SH3 and multiple ankyrin repeat domains protein 2 is a protein that in humans is encoded by the SHANK2 gene. Two alternative splice variants, encoding distinct isoforms, are reported...
.