Biology:DLG4

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3]

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.[1] 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,[4] and is involved in anchoring synaptic proteins. Its direct and indirect binding partners include neuroligin, NMDA receptors, AMPA receptors, and potassium channels.[5] It plays an important role in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation.[6]

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.[7] 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.

Model organisms

Model organisms have been used in the study of DLG4 function. A knockout mouse line, called Dlg4tm1Grnt[15] was generated. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[13][16] Twenty five tests were carried out on mutant mice and seven significant abnormalities were observed.[13] Homozygous mutant animals had decreased body weight, atypical indirect calorimetry and DEXA data and a skin phenotype. Males also had abnormal plasma chemistry while females had abnormal haematology (a decreased mean corpuscular haemoglobin count).[13]

Interactions

PSD-95 has been shown to interact with:


See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: DLG4 discs, large homolog 4 (Drosophila)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1742. 
  2. ↑ "The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein.". Neuron 9 (5): 929–942. Nov 1992. doi:10.1016/0896-6273(92)90245-9. PMID 1419001. 
  3. ↑ "Human postsynaptic density-95 (PSD95): location of the gene (DLG4) and possible function in nonneural as well as in neural tissues". Genomics 44 (1): 71–82. Nov 1997. doi:10.1006/geno.1997.4848. PMID 9286702. 
  4. ↑ "PSD-95 is associated with the postsynaptic density and not with the presynaptic membrane at forebrain synapses.". Journal of Neuroscience 16 (4): 1380–1388. Feb 1996. doi:10.1523/JNEUROSCI.16-04-01380.1996. PMID 8778289. 
  5. ↑ "PDZ domains and the organization of supramolecular complexes". Annu. Rev. Neurosci. 24: 1–29. 2001. doi:10.1146/annurev.neuro.24.1.1. PMID 11283303. 
  6. ↑ "Balance and stability of synaptic structures during synaptic plasticity". Neuron 82 (2): 430–43. 2014. doi:10.1016/j.neuron.2014.02.031. PMID 24742464. 
  7. ↑ "ZO-1, DlgA and PSD-95/SAP90: homologous proteins in tight, septate and synaptic cell junctions". Mech. Dev. 44 (2–3): 85–9. December 1993. doi:10.1016/0925-4773(93)90059-7. PMID 8155583. 
  8. ↑ "Body weight data for Dlg4". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAOR/weight-curves/. 
  9. ↑ "Indirect calorimetry data for Dlg4". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAOR/indirect-calorimetry/. 
  10. ↑ "DEXA data for Dlg4". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAOR/body-composition-dexa/. 
  11. ↑ "Clinical chemistry data for Dlg4". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAOR/plasma-chemistry/. 
  12. ↑ "Haematology data for Dlg4". Wellcome Trust Sanger Institute. http://www.sanger.ac.uk/mouseportal/phenotyping/MAOR/haematology-cbc/. 
  13. ↑ 13.0 13.1 13.2 13.3 Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  14. ↑ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  15. ↑ "Mouse Genome Informatics". http://www.informatics.jax.org/searchtool/Search.do?query=MGI:2182460. 
  16. ↑ "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. 2011. doi:10.1186/gb-2011-12-6-224. PMID 21722353. 
  17. ↑ 17.0 17.1 "Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission". Science 313 (5794): 1792–5. September 2006. doi:10.1126/science.1129947. PMID 16990550. Bibcode: 2006Sci...313.1792F. 
  18. ↑ "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". J. Biol. Chem. 275 (49): 38659–66. December 2000. doi:10.1074/jbc.M005938200. PMID 10995758. 
  19. ↑ "Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms". Nature 408 (6815): 936–43. 2000. doi:10.1038/35050030. PMID 11140673. Bibcode: 2000Natur.408..936C. 
  20. ↑ "Phosphorylation of stargazin by protein kinase A regulates its interaction with PSD-95". J. Biol. Chem. 277 (14): 12359–63. April 2002. doi:10.1074/jbc.M200528200. PMID 11805122. 
  21. ↑ 21.0 21.1 "Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms". J. Neurosci. 22 (15): 6415–25. August 2002. doi:10.1523/JNEUROSCI.22-15-06415.2002. PMID 12151521. 
  22. ↑ "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". J. Biol. Chem. 274 (9): 5782–90. February 1999. doi:10.1074/jbc.274.9.5782. PMID 10026200. 
  23. ↑ 23.0 23.1 23.2 23.3 "Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein". J. Neurosci. 20 (12): 4524–34. June 2000. doi:10.1523/JNEUROSCI.20-12-04524.2000. PMID 10844022. 
  24. ↑ 24.0 24.1 "SAPAPs. A family of PSD-95/SAP90-associated proteins localized at postsynaptic density". J. Biol. Chem. 272 (18): 11943–51. May 1997. doi:10.1074/jbc.272.18.11943. PMID 9115257. 
  25. ↑ 25.0 25.1 "Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family". Biochem. Biophys. Res. Commun. 264 (1): 247–52. October 1999. doi:10.1006/bbrc.1999.1489. PMID 10527873. 
  26. ↑ 26.0 26.1 "DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95". Genes Cells 2 (6): 415–24. June 1997. doi:10.1046/j.1365-2443.1997.1310329.x. PMID 9286858. 
  27. ↑ "Intramolecular interactions regulate SAP97 binding to GKAP". EMBO J. 19 (21): 5740–51. November 2000. doi:10.1093/emboj/19.21.5740. PMID 11060025. 
  28. ↑ "GKAP, a Novel Synaptic Protein That Interacts with the Guanylate Kinase-like Domain of the PSD-95/SAP90 Family of Channel Clustering Molecules". J. Cell Biol. 136 (3): 669–78. February 1997. doi:10.1083/jcb.136.3.669. PMID 9024696. 
  29. ↑ 29.0 29.1 "Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses". Neuron 26 (2): 443–55. May 2000. doi:10.1016/S0896-6273(00)81176-9. PMID 10839362. 
  30. ↑ "The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3596–601. March 2000. doi:10.1073/pnas.070042497. PMID 10725395. 
  31. ↑ 31.0 31.1 "NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex". Nat. Cell Biol. 5 (6): 520–30. June 2003. doi:10.1038/ncb990. PMID 12738960. 
  32. ↑ "Exocyst complex subunit sec8 binds to postsynaptic density protein-95 (PSD-95): a novel interaction regulated by cypin (cytosolic PSD-95 interactor)". Biochem. J. 373 (Pt 1): 49–55. July 2003. doi:10.1042/BJ20021838. PMID 12675619. 
  33. ↑ 33.0 33.1 "Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia". Brain Res. 955 (1–2): 123–32. November 2002. doi:10.1016/S0006-8993(02)03376-0. PMID 12419528. 
  34. ↑ "PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-d-aspartate receptor subunit NR2A". Proc. Natl. Acad. Sci. U.S.A. 96 (2): 435–40. January 1999. doi:10.1073/pnas.96.2.435. PMID 9892651. Bibcode: 1999PNAS...96..435T. 
  35. ↑ "Direct interaction of Frizzled-1, -2, -4, and -7 with PDZ domains of PSD-95". FEBS Lett. 521 (1–3): 185–9. June 2002. doi:10.1016/S0014-5793(02)02831-4. PMID 12067714. 
  36. ↑ "Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP". Neuron 37 (4): 625–38. February 2003. doi:10.1016/S0896-6273(02)01191-1. PMID 12597860. 
  37. ↑ 37.0 37.1 "Molecular mechanisms regulating the differential association of kainate receptor subunits with SAP90/PSD-95 and SAP97". J. Biol. Chem. 276 (19): 16092–9. May 2001. doi:10.1074/jbc.M100643200. PMID 11279111. 
  38. ↑ 38.0 38.1 "SAP90 binds and clusters kainate receptors causing incomplete desensitization". Neuron 21 (4): 727–39. October 1998. doi:10.1016/S0896-6273(00)80590-5. PMID 9808460. 
  39. ↑ 39.0 39.1 39.2 "Binding of neuroligins to PSD-95". Science 277 (5331): 1511–5. September 1997. doi:10.1126/science.277.5331.1511. PMID 9278515. 
  40. ↑ "A developmental change in NMDA receptor-associated proteins at hippocampal synapses". J. Neurosci. 20 (3): 1260–71. February 2000. doi:10.1523/JNEUROSCI.20-03-01260.2000. PMID 10648730. 
  41. ↑ 41.0 41.1 "Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102". J. Biol. Chem. 277 (24): 21697–711. June 2002. doi:10.1074/jbc.M112339200. PMID 11937501. 
  42. ↑ 42.0 42.1 42.2 "Inward rectifier K+ channel Kir2.3 is localized at the postsynaptic membrane of excitatory synapses". Am. J. Physiol., Cell Physiol. 282 (6): C1396–403. June 2002. doi:10.1152/ajpcell.00615.2001. PMID 11997254. 
  43. ↑ 43.0 43.1 "CRIPT, a novel postsynaptic protein that binds to the third PDZ domain of PSD-95/SAP90". Neuron 20 (4): 693–707. April 1998. doi:10.1016/S0896-6273(00)81009-0. PMID 9581762. 
  44. ↑ "Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95". Science 269 (5231): 1737–40. September 1995. doi:10.1126/science.7569905. PMID 7569905. Bibcode: 1995Sci...269.1737K. 
  45. ↑ 45.0 45.1 45.2 "N-terminal PDZ-binding domain in Kv1 potassium channels". FEBS Lett. 531 (3): 529–37. November 2002. doi:10.1016/S0014-5793(02)03572-X. PMID 12435606. 
  46. ↑ "Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases". Neuropharmacology 35 (7): 993–1000. 1996. doi:10.1016/0028-3908(96)00093-7. PMID 8938729. 
  47. ↑ "SAP97 increases Kv1.5 currents through an indirect N-terminal mechanism". FEBS Lett. 547 (1–3): 205–11. July 2003. doi:10.1016/S0014-5793(03)00668-9. PMID 12860415. 
  48. ↑ "A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels". J. Biol. Chem. 279 (18): 19051–63. April 2004. doi:10.1074/jbc.M400284200. PMID 14960569. 
  49. ↑ "Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins". J. Biol. Chem. 279 (21): 22331–46. May 2004. doi:10.1074/jbc.M400285200. PMID 15024025. 
  50. ↑ 50.0 50.1 "Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family". J. Neurosci. 20 (1): 156–62. January 2000. doi:10.1523/JNEUROSCI.20-01-00156.2000. PMID 10627592. 
  51. ↑ 51.0 51.1 "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". J. Biol. Chem. 275 (33): 25616–24. August 2000. doi:10.1074/jbc.M000955200. PMID 10827173. 
  52. ↑ "Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins". Biochem. J. 373 (Pt 2): 381–91. July 2003. doi:10.1042/BJ20021958. PMID 12713445. 
  53. ↑ "CAPON: a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95". Neuron 20 (1): 115–24. January 1998. doi:10.1016/S0896-6273(00)80439-0. PMID 9459447. 
  54. ↑ "Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains". Cell 84 (5): 757–67. March 1996. doi:10.1016/S0092-8674(00)81053-3. PMID 8625413. 
  55. ↑ "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". J. Biol. Chem. 278 (17): 15040–8. April 2003. doi:10.1074/jbc.M212825200. PMID 12576483. 
  56. ↑ "Sema4c, a transmembrane semaphorin, interacts with a post-synaptic density protein, PSD-95". J. Biol. Chem. 276 (12): 9174–81. March 2001. doi:10.1074/jbc.M009051200. PMID 11134026. 

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