PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''DLG4'' (discs large homolog 4)

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. PSD-95 is a member of the

membrane-associated guanylate kinase The membrane-associated guanylate kinases (MAGUK) 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. The G ...

(MAGUK) family. With PSD-93 it is recruited into the same

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...

and

potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...

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 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. Proteins containing PDZ domains play a key role in anchoring receptor proteins in the membrane to cy ...

-containing proteins. Like all MAGUK-family proteins, its basic structure includes three PDZ domains, an

SH3 domain The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phos ...

, and a guanylate kinase-like domain (GK) connected by disordered linker regions. It is almost exclusively located in the post synaptic density of

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s, and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include

neuroligin Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell ad ...

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...

s, and

s. It plays an important role in

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuit ...

and the stabilization of synaptic changes during

long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...

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-93,

SAP97 Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the ''SAP97'' gene. SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein ...

and SAP102. The MAGUKs are defined by their inclusion of PDZ, SH3 and

GUK ''Guk'' (), also sometimes known as ''tang'' (), is a class of soup-like dishes in Korean cuisine. ''Guk'' and ''tang'' are commonly grouped together and regarded as the same type of dish, although ''tang'' can sometimes be less watery than ...

domains, although many of them also contain regions homologous of

CaMKII /calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the / calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediato ...

, WW and L27 domains. The GUK domain that they have is structurally very similar to that of the

guanylate kinase In enzymology, a guanylate kinase () is an enzyme that catalyzes the chemical reaction : ATP + GMP \rightleftharpoons ADP + GDP Thus, the two substrates of this enzyme are ATP and GMP, whereas its two product (chemistry), products are adeno ...

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

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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

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 an 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 (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...

binding region located elsewhere in the gene.

Model organisms

Model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

s have been used in the study of DLG4 function. A

knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

line, called ''Dlg4^tm1Grnt'' was generated. Male and female animals underwent a standardized

phenotypic screen In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

to determine the effects of deletion. Twenty five tests were carried out on

mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...

mice and seven significant abnormalities were observed. Homozygous mutant animals had decreased body weight, atypical

indirect calorimetry Indirect calorimetry calculates heat that living organisms produce by measuring either their production of carbon dioxide and nitrogen waste (frequently ammonia in aquatic organisms, or urea in terrestrial ones), or from their consumption of oxyg ...

and

DEXA Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracted ...

data and a skin phenotype. Males also had abnormal

plasma chemistry Gas phase ion chemistry is a field of science encompassed within both chemistry and physics. It is the science that studies ions and molecules in the gas phase, most often enabled by some form of mass spectrometry. By far the most important applic ...

while females had abnormal haematology (a decreased mean corpuscular

haemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...

count).

Interactions

PSD-95 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

ADAM22 Adam John Grandmaison (born November 24, 1983), more commonly known as Adam22, is an American podcaster and YouTuber. He is best known for being the creator and host of pop culture-oriented podcast ''No Jumper''.Grierson, Tim. How Adam22 Tur ...

Beta-1 adrenergic receptor The beta-1 adrenergic receptor (β1 adrenoceptor), also known as ADRB1, is a beta-adrenergic receptor, and also denotes the human gene encoding it. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein and is express ...

CACNG2 Calcium 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 L-type calcium channels are composed of five subunits. The protein encoded by this gen ...

CASK A barrel or cask is a hollow cylindrical container with a bulging center, longer than it is wide. They are traditionally made of wooden staves and bound by wooden or metal hoops. The word vat is often used for large containers for liquids, u ...

DLG3 Disks large homolog 3 (DLG3) also known as neuroendocrine-DLG or synapse-associated protein 102 (SAP-102) is a protein that in humans is encoded by the ''DLG3'' gene. DLG3 is a member of the membrane-associated guanylate kinase (MAGUK) superfamily ...

DLGAP1 Disks large-associated protein 1 (DAP-1), also known as guanylate kinase-associated protein (GKAP), 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 p ...

DLGAP2 Disks large-associated protein 2 is a protein that in humans is encoded by the ''DLGAP2'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''genera ...

DYNLL1 Dynein light chain 1, cytoplasmic is a protein that in humans is encoded by the ''DYNLL1'' gene. Function Cytoplasmic dyneins are large enzyme complexes with a molecular mass of about 1,200 kD. They contain two force-producing heads formed prim ...

DYNLL2 Dynein 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, C12orf40, DLGAP1, MYO5A Unconventional myosin-Va is a motor protein in charge of the in ...

ERBB4 Receptor 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 characteriz ...

EXOC4 Exocyst complex component 4 is a protein that in humans is encoded by the ''EXOC4'' gene. Function The protein encoded by this gene is a component of the exocyst complex, a multiple protein complex essential for targeting exocytic vesicles to ...

FYN Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...

FZD7 Frizzled-7 (Fd-7) is a protein that in humans is encoded by the ''FZD7'' gene. Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD7 protein contains an N-terminal si ...

GRIK1 Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the ''GRIK1'' gene. Function This gene encodes one of the many ionotropic glutamate receptor (GluR) subunits that function as a ligand-ga ...

GRIK2 Glutamate ionotropic receptor kainate type subunit 2, also known as ionotropic glutamate receptor 6 or GluR6, is a protein that in humans is encoded by the ''GRIK2'' (or ''GLUR6'') gene. Function This gene encodes a subunit of a kainate glut ...

GRIK5 Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the ''GRIK5'' gene. Function This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory n ...

GRIN2A Glutamate MDAreceptor subunit epsilon-1 is a protein that in humans is encoded by the ''GRIN2A'' gene. The canonical GluN2A subunit isoform encompasses 1464 amino acids. Alternative splicing can generate a primate-specific GluN2A-short isoform (12 ...

GRIN2B Glutamate MDAreceptor subunit epsilon-2, also known as ''N''-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the ''GRIN2B'' gene. NMDA receptors ''N''-methyl-D-aspartate (NMDA) receptors are a ...

GRIN2C Glutamate MDAreceptor subunit epsilon-3 is a protein that in humans is encoded by the ''GRIN2C'' gene. Function N-methyl-D-aspartate (NMDA) receptors are a class of ionotropic glutamate receptors. NMDA channel has been shown to be involved in ...

HER2/neu Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

* HGS *

KCNA2 Potassium voltage-gated channel subfamily A member 2 also known as Kv1.2 is a protein that in humans is encoded by the ''KCNA2'' gene. Function Potassium channels represent the most complex class of voltage-gated ion channels from both function ...

KCNA4 Potassium 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 (Ito1), the main contributing current to the ...

KCNA5 Potassium 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 Potassium channels represent the most complex class of voltage-gated ion ...

KCNJ12 ATP-sensitive inward rectifier potassium channel 12 is a lipid-gated ion channel that in humans is encoded by the ''KCNJ12'' gene. Function This gene encodes an inwardly rectifying K+ channel that may be blocked by divalent cations. This pro ...

Kir2.1 The Kir2.1 inward-rectifier potassium channel is a lipid-gated ion channel encoded by the gene. Clinical significance A defect in this gene is associated with Andersen-Tawil syndrome. A mutation in the KCNJ2 gene has also been shown to c ...

LGI1 Leucine-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 The leucine-rich glioma inactivated -1 gene is rearranged as a result of transloc ...

LRP1 Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membr ...

LRP2 Low density lipoprotein receptor-related protein 2 also known as LRP-2 or megalin is a protein which in humans is encoded by the ''LRP2'' gene. Function LRP2 was identified as the antigen of rat experimental membranous nephropathy (Heyman neph ...

NLGN1 Neuroligin-1 is a protein that in humans is encoded by the ''NLGN1'' gene. This gene encodes a member of the neuroligin family of neuronal cell surface proteins. Neuroligin-1 acts as splice site-specific ligand for β-neurexins and has been shown ...

NOS1 Nitric oxide synthase 1 (neuronal), also known as NOS1, is an enzyme that in humans is encoded by the ''NOS1'' gene. Function Nitric oxide synthases () (NOSs) are a family of synthases that catalysis, catalyze the production of nitric oxide (NO ...

PTK2B Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the ''PTK2B'' gene. Function This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the ...

SEMA4C Semaphorin-4C is a protein that in humans is encoded by the ''SEMA4C'' gene. Interactions SEMA4C has been shown to interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit org ...

and *

SHANK2 SH3 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. Additional splice variants exist but their full-length natur ...

References

External links

* {{MeshName, DLG4+protein,+human, 3=DLG4 protein, human Genes mutated in mice

MAGUK superfamily and constituent domains

Model organisms

Interactions

See also

References

External links