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DLG4

{{Short description|Mammalian protein found in Homo sapiens}}

{{Infobox_gene}}

PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the DLG4 (discs large homolog 4) gene.{{cite journal|author-link3= Mary B. Kennedy |vauthors=Cho KO, Hunt CA, Kennedy MB | title = The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein. | journal = Neuron | volume = 9 | issue = 5 | pages = 929–942 |date=Nov 1992 | pmid = 1419001 | doi=10.1016/0896-6273(92)90245-9|s2cid=28528759 }}{{cite journal |vauthors=Stathakis DG, Hoover KB, You Z, Bryant PJ | title = Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues | journal = Genomics | volume = 44 | issue = 1 | pages = 71–82 |date=Nov 1997 | pmid = 9286702 | doi = 10.1006/geno.1997.4848 }}

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.{{Cite web| title = Entrez Gene: DLG4 discs, large homolog 4 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1742}}

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 neurons,{{cite journal |vauthors=Hunt CA, Schenker LJ, Kennedy MB | title = PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses. | journal = Journal of Neuroscience | volume = 16 | issue = 4 | pages = 1380–1388 |date=Feb 1996 | pmid = 8778289 | pmc = 6578559 | doi = 10.1523/JNEUROSCI.16-04-01380.1996 }} and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels.{{cite journal |vauthors=Sheng M, Sala C | title = PDZ domains and the organization of supramolecular complexes | journal = Annu. Rev. Neurosci. | volume = 24 | pages = 1–29 | year = 2001 | pmid = 11283303 | doi = 10.1146/annurev.neuro.24.1.1 }} It plays an important role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.{{cite journal |vauthors=Meyer D, Bonhoeffer T, Scheuss V | title = Balance and stability of synaptic structures during synaptic plasticity | journal = Neuron | volume = 82 | issue = 2 | pages = 430–43 | year = 2014 | pmid = 24742464 | doi = 10.1016/j.neuron.2014.02.031 | doi-access = free }}

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 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.{{cite journal |vauthors=Woods DF, Bryant PJ | title = ZO-1, DlgA and PSD-95/SAP90: homologous proteins in tight, septate and synaptic cell junctions | journal = Mech. Dev. | volume = 44 | issue = 2–3 | pages = 85–9 |date=December 1993 | pmid = 8155583 | doi = 10.1016/0925-4773(93)90059-7| s2cid = 5785380 }} The GUK domain that they have is structurally very similar to that of the guanylate kinases, 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 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 binding region located elsewhere in the gene.

Interactions

PSD-95 has been shown to interact with:

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  • ADAM22{{cite journal |vauthors=Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M | title = Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission | journal = Science | volume = 313 | issue = 5794 | pages = 1792–5 |date=September 2006 | pmid = 16990550 | doi = 10.1126/science.1129947 | bibcode = 2006Sci...313.1792F | s2cid = 33024022 }}
  • Beta-1 adrenergic receptor{{cite journal |vauthors=Hu LA, Tang Y, Miller WE, Cong M, Lau AG, Lefkowitz RJ, Hall RA | title = beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors | journal = J. Biol. Chem. | volume = 275 | issue = 49 | pages = 38659–66 |date=December 2000 | pmid = 10995758 | doi = 10.1074/jbc.M005938200 | doi-access = free }}
  • CACNG2{{cite journal |vauthors=Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA | title = Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms | journal = Nature | volume = 408 | issue = 6815 | pages = 936–43 | year = 2000 | pmid = 11140673 | doi = 10.1038/35050030 | bibcode = 2000Natur.408..936C | s2cid = 4427689 }}{{cite journal |vauthors=Choi J, Ko J, Park E, Lee JR, Yoon J, Lim S, Kim E | title = Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95 | journal = J. Biol. Chem. | volume = 277 | issue = 14 | pages = 12359–63 |date=April 2002 | pmid = 11805122 | doi = 10.1074/jbc.M200528200 | doi-access = free }}
  • CASK{{cite journal |vauthors=Chetkovich DM, Bunn RC, Kuo SH, Kawasaki Y, Kohwi M, Bredt DS | title = Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms | journal = J. Neurosci. | volume = 22 | issue = 15 | pages = 6415–25 |date=August 2002 | pmid = 12151521 | pmc = 6758133 | doi = 10.1523/JNEUROSCI.22-15-06415.2002}}
  • DLG3{{cite journal |vauthors=Masuko N, Makino K, Kuwahara H, Fukunaga K, Sudo T, Araki N, Yamamoto H, Yamada Y, Miyamoto E, Saya H | title = Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites | journal = J. Biol. Chem. | volume = 274 | issue = 9 | pages = 5782–90 |date=February 1999 | pmid = 10026200 | doi = 10.1074/jbc.274.9.5782 | doi-access = free }}
  • DLGAP1{{cite journal |vauthors=Naisbitt S, Valtschanoff J, Allison DW, Sala C, Kim E, Craig AM, Weinberg RJ, Sheng M | title = Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein | journal = J. Neurosci. | volume = 20 | issue = 12 | pages = 4524–34 |date=June 2000 | pmid = 10844022 | pmc = 6772433 | doi = 10.1523/JNEUROSCI.20-12-04524.2000}}{{cite journal |vauthors=Takeuchi M, Hata Y, Hirao K, Toyoda A, Irie M, Takai Y | title = SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density | journal = J. Biol. Chem. | volume = 272 | issue = 18 | pages = 11943–51 |date=May 1997 | pmid = 9115257 | doi = 10.1074/jbc.272.18.11943| doi-access = free }}{{cite journal |vauthors=Boeckers TM, Winter C, Smalla KH, Kreutz MR, Bockmann J, Seidenbecher C, Garner CC, Gundelfinger ED | title = Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family | journal = Biochem. Biophys. Res. Commun. | volume = 264 | issue = 1 | pages = 247–52 |date=October 1999 | pmid = 10527873 | doi = 10.1006/bbrc.1999.1489 }}{{cite journal |vauthors=Satoh K, Yanai H, Senda T, Kohu K, Nakamura T, Okumura N, Matsumine A, Kobayashi S, Toyoshima K, Akiyama T | title = DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95 | journal = Genes Cells | volume = 2 | issue = 6 | pages = 415–24 |date=June 1997 | pmid = 9286858 | doi = 10.1046/j.1365-2443.1997.1310329.x | s2cid = 8934092 | doi-access = free }}{{cite journal |vauthors=Wu H, Reissner C, Kuhlendahl S, Coblentz B, Reuver S, Kindler S, Gundelfinger ED, Garner CC | title = Intramolecular interactions regulate SAP97 binding to GKAP | journal = EMBO J. | volume = 19 | issue = 21 | pages = 5740–51 |date=November 2000 | pmid = 11060025 | pmc = 305801 | doi = 10.1093/emboj/19.21.5740 }}{{cite journal |vauthors=Kim E, Naisbitt S, Hsueh YP, Rao A, Rothschild A, Craig AM, Sheng M | title = GKAP, a Novel Synaptic Protein That Interacts with the Guanylate Kinase-like Domain of the PSD-95/SAP90 Family of Channel Clustering Molecules | journal = J. Cell Biol. | volume = 136 | issue = 3 | pages = 669–78 |date=February 1997 | pmid = 9024696 | pmc = 2134290 | doi = 10.1083/jcb.136.3.669}}
  • DLGAP2
  • DYNLL1
  • DYNLL2
  • ERBB4{{cite journal |vauthors=Garcia RA, Vasudevan K, Buonanno A | title = The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 7 | pages = 3596–601 |date=March 2000 | pmid = 10725395 | pmc = 16285 | doi = 10.1073/pnas.070042497 | doi-access = free }}
  • EXOC4{{cite journal |vauthors=Riefler GM, Balasingam G, Lucas KG, Wang S, Hsu SC, Firestein BL | title = Exocyst complex subunit sec8 binds to postsynaptic density protein-95 (PSD-95): a novel interaction regulated by cypin (cytosolic PSD-95 interactor) | journal = Biochem. J. | volume = 373 | issue = Pt 1 | pages = 49–55 |date=July 2003 | pmid = 12675619 | pmc = 1223477 | doi = 10.1042/BJ20021838 }}
  • FYN{{cite journal |vauthors=Tezuka T, Umemori H, Akiyama T, Nakanishi S, Yamamoto T | title = PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-d-aspartate receptor subunit NR2A | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 2 | pages = 435–40 |date=January 1999 | pmid = 9892651 | pmc = 15154 | doi = 10.1073/pnas.96.2.435 | bibcode = 1999PNAS...96..435T | doi-access = free }}
  • FZD7{{cite journal |vauthors=Hering H, Sheng M | title = Direct interaction of Frizzled-1, -2, -4, and -7 with PDZ domains of PSD-95 | journal = FEBS Lett. | volume = 521 | issue = 1–3 | pages = 185–9 |date=June 2002 | pmid = 12067714 | doi = 10.1016/S0014-5793(02)02831-4 | s2cid = 39243103 | doi-access = free }}
  • GRIK1{{cite journal |vauthors=Hirbec H, Francis JC, Lauri SE, Braithwaite SP, Coussen F, Mulle C, Dev KK, Coutinho V, Meyer G, Isaac JT, Collingridge GL, Henley JM, Couthino V | title = Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP | journal = Neuron | volume = 37 | issue = 4 | pages = 625–38 |date=February 2003 | pmid = 12597860 | doi = 10.1016/S0896-6273(02)01191-1 | pmc=3314502}}
  • GRIK2{{cite journal |vauthors=Mehta S, Wu H, Garner CC, Marshall J | title = Molecular mechanisms regulating the differential association of kainate receptor subunits with SAP90/PSD-95 and SAP97 | journal = J. Biol. Chem. | volume = 276 | issue = 19 | pages = 16092–9 |date=May 2001 | pmid = 11279111 | doi = 10.1074/jbc.M100643200 | doi-access = free }}{{cite journal |vauthors=Garcia EP, Mehta S, Blair LA, Wells DG, Shang J, Fukushima T, Fallon JR, Garner CC, Marshall J | title = SAP90 binds and clusters kainate receptors causing incomplete desensitization | journal = Neuron | volume = 21 | issue = 4 | pages = 727–39 |date=October 1998 | pmid = 9808460 | doi = 10.1016/S0896-6273(00)80590-5 | s2cid = 18723258 | doi-access = free }}
  • GRIK5
  • GRIN2A{{cite journal |vauthors=Hou XY, Zhang GY, Yan JZ, Chen M, Liu Y | title = Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia | journal = Brain Res. | volume = 955 | issue = 1–2 | pages = 123–32 |date=November 2002 | pmid = 12419528 | doi = 10.1016/S0006-8993(02)03376-0 | s2cid = 85751 }}{{cite journal |vauthors=Irie M, Hata Y, Takeuchi M, Ichtchenko K, Toyoda A, Hirao K, Takai Y, Rosahl TW, Südhof TC | title = Binding of neuroligins to PSD-95 | journal = Science | volume = 277 | issue = 5331 | pages = 1511–5 |date=September 1997 | pmid = 9278515 | doi = 10.1126/science.277.5331.1511 }}{{cite journal |vauthors=Sans N, Petralia RS, Wang YX, Blahos J, Hell JW, Wenthold RJ | title = A developmental change in NMDA receptor-associated proteins at hippocampal synapses | journal = J. Neurosci. | volume = 20 | issue = 3 | pages = 1260–71 |date=February 2000 | pmid = 10648730 | pmc = 6774158 | doi = 10.1523/JNEUROSCI.20-03-01260.2000}}
  • GRIN2B{{cite journal |vauthors=Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ | title = NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex | journal = Nat. Cell Biol. | volume = 5 | issue = 6 | pages = 520–30 |date=June 2003 | pmid = 12738960 | doi = 10.1038/ncb990 | s2cid = 13444388 }}{{cite journal |vauthors=Niethammer M, Valtschanoff JG, Kapoor TM, Allison DW, Weinberg RJ, Craig AM, Sheng M | title = CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90 | journal = Neuron | volume = 20 | issue = 4 | pages = 693–707 |date=April 1998 | pmid = 9581762 | doi = 10.1016/S0896-6273(00)81009-0 | s2cid = 16068361 | doi-access = free }}{{cite journal |vauthors=Kornau HC, Schenker LT, Kennedy MB, Seeburg PH | title = Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95 | journal = Science | volume = 269 | issue = 5231 | pages = 1737–40 |date=September 1995 | pmid = 7569905 | doi = 10.1126/science.7569905 | bibcode = 1995Sci...269.1737K }}
  • GRIN2C{{cite journal |vauthors=Lim IA, Hall DD, Hell JW | title = Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102 | journal = J. Biol. Chem. | volume = 277 | issue = 24 | pages = 21697–711 |date=June 2002 | pmid = 11937501 | doi = 10.1074/jbc.M112339200 | doi-access = free }}
  • HER2/neu{{cite journal |vauthors=Huang YZ, Won S, Ali DW, Wang Q, Tanowitz M, Du QS, Pelkey KA, Yang DJ, Xiong WC, Salter MW, Mei L | title = Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses | journal = Neuron | volume = 26 | issue = 2 | pages = 443–55 |date=May 2000 | pmid = 10839362 | doi = 10.1016/S0896-6273(00)81176-9 | s2cid = 1429113 | doi-access = free }}
  • HGS
  • KCNA2
  • KCNA4{{cite journal |vauthors=Kim E, Sheng M | title = Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases | journal = Neuropharmacology | volume = 35 | issue = 7 | pages = 993–1000 | year = 1996 | pmid = 8938729 | doi = 10.1016/0028-3908(96)00093-7 | s2cid = 23755452 }}
  • KCNA5{{cite journal |vauthors=Eldstrom J, Doerksen KW, Steele DF, Fedida D | title = N-terminal PDZ-binding domain in Kv1 potassium channels | journal = FEBS Lett. | volume = 531 | issue = 3 | pages = 529–37 |date=November 2002 | pmid = 12435606 | doi = 10.1016/S0014-5793(02)03572-X | s2cid = 40689829 | doi-access = free }}{{cite journal |vauthors=Eldstrom J, Choi WS, Steele DF, Fedida D | title = SAP97 increases Kv1.5 currents through an indirect N-terminal mechanism | journal = FEBS Lett. | volume = 547 | issue = 1–3 | pages = 205–11 |date=July 2003 | pmid = 12860415 | doi = 10.1016/S0014-5793(03)00668-9 | s2cid = 34857270 | doi-access = free }}
  • KCNJ12{{cite journal |vauthors=Inanobe A, Fujita A, Ito M, Tomoike H, Inageda K, Kurachi Y | title = Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses | journal = Am. J. Physiol., Cell Physiol. | volume = 282 | issue = 6 | pages = C1396–403 |date=June 2002 | pmid = 11997254 | doi = 10.1152/ajpcell.00615.2001}}{{cite journal |vauthors=Leonoudakis D, Conti LR, Radeke CM, McGuire LM, Vandenberg CA | title = A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels | journal = J. Biol. Chem. | volume = 279 | issue = 18 | pages = 19051–63 |date=April 2004 | pmid = 14960569 | doi = 10.1074/jbc.M400284200 | doi-access = free }}{{cite journal |vauthors=Leonoudakis D, Conti LR, Anderson S, Radeke CM, McGuire LM, Adams ME, Froehner SC, Yates JR, Vandenberg CA | title = Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins | journal = J. Biol. Chem. | volume = 279 | issue = 21 | pages = 22331–46 |date=May 2004 | pmid = 15024025 | doi = 10.1074/jbc.M400285200 | doi-access = free }}
  • Kir2.1{{cite journal |vauthors=Nehring RB, Wischmeyer E, Döring F, Veh RW, Sheng M, Karschin A | title = Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family | journal = J. Neurosci. | volume = 20 | issue = 1 | pages = 156–62 |date=January 2000 | pmid = 10627592 | pmc = 6774109 | doi = 10.1523/JNEUROSCI.20-01-00156.2000}}
  • LGI1
  • LRP1
  • LRP2{{cite journal |vauthors=Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J | title = Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction | journal = J. Biol. Chem. | volume = 275 | issue = 33 | pages = 25616–24 |date=August 2000 | pmid = 10827173 | doi = 10.1074/jbc.M000955200 | doi-access = free }}{{cite journal |vauthors=Larsson M, Hjälm G, Sakwe AM, Engström A, Höglund AS, Larsson E, Robinson RC, Sundberg C, Rask L | title = Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins | journal = Biochem. J. | volume = 373 | issue = Pt 2 | pages = 381–91 |date=July 2003 | pmid = 12713445 | pmc = 1223512 | doi = 10.1042/BJ20021958 }}
  • NLGN1
  • NOS1{{cite journal |vauthors=Jaffrey SR, Snowman AM, Eliasson MJ, Cohen NA, Snyder SH | title = CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95 | journal = Neuron | volume = 20 | issue = 1 | pages = 115–24 |date=January 1998 | pmid = 9459447 | doi = 10.1016/S0896-6273(00)80439-0 | s2cid = 14613261 | doi-access = free }}{{cite journal |vauthors=Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, Froehner SC, Bredt DS | title = Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains | journal = Cell | volume = 84 | issue = 5 | pages = 757–67 |date=March 1996 | pmid = 8625413 | doi = 10.1016/S0092-8674(00)81053-3 | s2cid = 15834673 | doi-access = free }}
  • PTK2B{{cite journal |vauthors=Seabold GK, Burette A, Lim IA, Weinberg RJ, Hell JW | title = Interaction of the tyrosine kinase Pyk2 with the N-methyl-D-aspartate receptor complex via the Src homology 3 domains of PSD-95 and SAP102 | journal = J. Biol. Chem. | volume = 278 | issue = 17 | pages = 15040–8 |date=April 2003 | pmid = 12576483 | doi = 10.1074/jbc.M212825200 | doi-access = free }}
  • SEMA4C{{cite journal |vauthors=Inagaki S, Ohoka Y, Sugimoto H, Fujioka S, Amazaki M, Kurinami H, Miyazaki N, Tohyama M, Furuyama T | title = Sema4c, a transmembrane semaphorin, interacts with a post-synaptic density protein, PSD-95 | journal = J. Biol. Chem. | volume = 276 | issue = 12 | pages = 9174–81 |date=March 2001 | pmid = 11134026 | doi = 10.1074/jbc.M009051200 | doi-access = free }} and
  • SHANK2.

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See also

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References

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External links

  • {{MeshName|DLG4+protein,+human|3=DLG4 protein, human}}

Category:Genes mutated in mice