Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Carlos Oliva
  • Jimena SierraltaEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101711


Historical Background

Membrane-associated guanylate kinases (MAGUKs) are a family of proteins generally involved in scaffolding. Functions for these proteins have been described in diverse cellular processes such as epithelial polarity and maintenance, cell-cell communication, synapse physiology, cell polarity, and signal transduction (Oliva et al. 2012). The protein family is characterized by the presence of a guanylate kinase (GK) domain, homologous to the bacterial guanylate kinase enzyme involved in the transfer of a phosphate group from ATP to GMP, essential in GTP synthesis (Li and Yan 1996; Zhu et al. 2012). However, in the MAGUK family, this domain is enzymatically inactive and instead mediates protein-protein interactions.

The founder members of the MAGUK family are the postsynaptic density proteins of 95 KDa (PSD95), Zonula Occludens 1 (ZO1) and the DrosophilaDiscs Large (DLG). They share a similar structure with PDZ...

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  1. Astorga C, Jorquera RA, Ramírez M, Kohler A, López E, Delgado R, et al. Presynaptic DLG regulates synaptic function through the localization of voltage-activated Ca2+ channels. Sci Rep. 2016;6:322132.CrossRefGoogle Scholar
  2. Bachmann A, Kobler O, Kittel RJ, Wichmann C, Sierralta J, Sigrist SJ, et al. A Perisynaptic menage a trois between Dlg, DLin-7, and metro controls proper organization of drosophila synaptic junctions. J Neurosci. 2010;30(17):5811–24.CrossRefPubMedGoogle Scholar
  3. Budnik V, Koh YH, Guan B, Hartmann B, Hough C, Woods D, et al. Regulation of synapse structure and function by the Drosophila tumor suppressor gene dlg. Neuron. 1996;17(4):627–40.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Chen X, Levy JM, Hou A, Winters C, Azzam R, Sousa AA, et al. PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. Proc Natl Acad Sci. 2015;112(50):E6983–92.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chetkovich DM, Chen L, Stocker TJ, Nicoll RA, Bredt DS. Phosphorylation of the postsynaptic density-95 (PSD-95)/discs large/zona occludens-1 binding site of stargazin regulates binding to PSD-95 and synaptic targeting of AMPA receptors. J Neurosci. 2002;22(14):5791–6.CrossRefPubMedGoogle Scholar
  6. Crocker-Buque A, Currie SP, Luz LL, Grant SG, Duffy KR, Kind PC, et al. Altered thalamocortical development in the SAP102 knockout model of intellectual disability. Hum Mol Genet. 2016.  https://doi.org/10.1093/hmg/ddw244.CrossRefPubMedPubMedCentralGoogle Scholar
  7. de Mendoza A, Suga H, Ruiz-Trillo I. Evolution of the MAGUK protein gene family in premetazoan lineages. BMC Evol Biol. 2010;10(1):93–10.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Elsum I, Yates L, Humbert PO, Richardson HE. The Scribble-Dlg-Lgl polarity module in development and cancer: from flies to man. Essays Biochem. 2012;53:141–68.CrossRefGoogle Scholar
  9. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506(7487):179–84.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Funke L, Dakoji S, Bredt DS. Membrane-associated guanylate kinases regulate adhesion and plasticity at cell juctions. Annu Rev Biochem. 2005;74:219–45.CrossRefPubMedGoogle Scholar
  11. Gillet L, Rougier J-S, Shy D, Sonntag S, Mougenot N, Essers M, et al. Cardiac-specific ablation of synapse-associated protein SAP97 in mice decreases potassium currents but not sodium current. Heart Rhythm. 2015;12(1):181–92.CrossRefPubMedGoogle Scholar
  12. Grant SGN. Synaptopathies: diseases of the synaptome. Curr Opin Neurobiol. 2012;22(3):522–9.CrossRefPubMedGoogle Scholar
  13. Grawe F, Wodarz A, Lee B, Knust E, Skaer H. The Drosophila genes crumbs and stardust are involved in the biogenesis of adherens junctions. Development. 1996 Mar;122(3):951–9.PubMedGoogle Scholar
  14. Harris BZ, Lim WA. Mechanism and role of PDZ domains in signaling complex assembly. J Cell Sci. 2001;114(18):3219–31.PubMedGoogle Scholar
  15. Hill WD, Davies G, van de Lagemaat LN, Christoforou A, Marioni RE, Fernandes CPD, et al. Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins. Transl Psychiatry. 2013;4(1):e341–8.CrossRefGoogle Scholar
  16. Hsueh Y-P. The role of the MAGUK protein CASK in neural development and synaptic function. Curr Med Chem. 2006;13(16):1915–27.CrossRefPubMedGoogle Scholar
  17. Hsueh YP, Wang TF, Yang FC, Sheng M. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Nature. 2000;404(6775):298–302.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Humphries LA, Shaffer MH, Sacirbegovic F, Tomassian T, McMahon K-A, Humbert PO, et al. Characterization of in vivo Dlg1 deletion on T cell development and function. PLoS One. 2012;7(9):e45276–19.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Kim E, Niethammer M, Rothschild A, Nung Jan Y, Sheng M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature. 1995;378(6552):85–8.CrossRefPubMedGoogle Scholar
  20. Kim E, Sheng M. PDZ domain proteins of synapses. Nat Rev Neurosci. 2004;5(10):771–81.CrossRefPubMedGoogle Scholar
  21. Koh YH, Popova E, Thomas U, Griffith LC, Budnik V. Regulation of DLG localization at synapses by CaMKII-dependent phosphorylation. Cell. 1999;98(3):353–63.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Li Y, Yan H. Kinetic and thermodynamic characterizations of yeast guanylate kinase. J Biol Chem. 1996;271(45):28038–44.CrossRefPubMedGoogle Scholar
  23. Liu J, Li J, Ren Y, Liu P. DLG5 in cell polarity maintenance and cancer development. Int J Biol Sci. 2014;10(5):543–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. McGee AW, Dakoji SR, Olsen O, Bredt DS, Lim WA. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol Cell. 2001;8(6):1291–301.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Mendoza-Topaz C, Urra F, Barria R, Albornoz V, Ugalde D, Thomas U, et al. DLGS97/SAP97 is developmentally upregulated and is required for complex adult behaviors and synapse morphology and function. J Neurosci. 2008;28(1):304–14.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Naim E, Bernstein A, Bertram JF, Caruana G. Mutagenesis of the epithelial polarity gene, discs large 1, perturbs nephrogenesis in the developing mouse kidney. Kidney Int. 2005;68(3):955–65.CrossRefPubMedGoogle Scholar
  27. Niethammer M, Kim E, Sheng M. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. J Neurosci. 1996;16(7):2157–63.CrossRefPubMedGoogle Scholar
  28. Oliva C, Escobedo P, Astorga C, Molina C, Sierralta J. Role of the MAGUK protein family in synapse formation and function. Dev Neurobiol. 2012;72(1):57–72.CrossRefPubMedGoogle Scholar
  29. Poglia L, Muller D, Nikonenko I. Ultrastructural modifications of spine and synapse morphology by SAP97. Hippocampus. 2011;21(9):990–8.PubMedGoogle Scholar
  30. Rivera C, Yamben IF, Shatadal S, Waldof M, Robinson ML, Griep AE. Cell-autonomous requirements for Dlg-1for lens epithelial cell structure and fiber cell morphogenesis. Dev Dyn. 2009;238(9):2292–308.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Roberts S, Delury C, Marsh E. The PDZ protein discs-large (DLG): the “Jekyll and Hyde” of the epithelial polarity proteins. FEBS J. 2012;279(19):3549–58.CrossRefPubMedGoogle Scholar
  32. Roche MI, Ramadas RA, Medoff BD. The role of CARMA1 in T cells. Crit Rev Immunol. 2013;33(3):219–43.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Sheng M, Hoogenraad CC. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu Rev Biochem. 2007;76(1):823–47.CrossRefPubMedGoogle Scholar
  34. Shin H, Hsueh YP, Yang FC, Kim E, Sheng M. An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90. J Neurosci. 2000;20(10):3580–7.CrossRefPubMedGoogle Scholar
  35. Thomas U, Kobler O, Gundelfinger ED. The Drosophila larval neuromuscular junction as a model for scaffold complexes at glutamatergic synapses: benefits and limitations. J Neurogenet. 2010;24(3):109–19.CrossRefPubMedGoogle Scholar
  36. Topinka JR, Bredt DS. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron. 1998;20(1):125–34.CrossRefPubMedGoogle Scholar
  37. Walch L. Emerging role of the scaffolding protein Dlg1 in vesicle trafficking. Traffic. 2013;14(9):964–73.CrossRefPubMedGoogle Scholar
  38. Woods DF, Bryant PJ. ZO-1, DlgA and PSD-95/SAP90: homologous proteins in tight, septate and synaptic cell junctions. Mech Dev. 1993;44(2–3):85–9.CrossRefPubMedGoogle Scholar
  39. Woods DF, Hough C, Peel D, Callaini G, Bryant PJ. Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia. J Cell Biol. 1996;134(6):1469–82.CrossRefPubMedGoogle Scholar
  40. Zhu J, Shang Y, Chen J, Zhang M. Structure and function of the guanylate kinase-like domain of the MAGUK family scaffold proteins. Front Biol. 2012;7(5):379–96.CrossRefGoogle Scholar
  41. Zhu J, Shang Y, Xia C, Wang W, Wen W, Zhang M. Guanylate kinase domains of the MAGUK family scaffold proteins as specific phospho-protein-binding modules. EMBO J. 2011;30(24):4986–97.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Zhu J, Shang Y, Zhang M. Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat Rev Neurosci. 2016;17(4):209–23.CrossRefPubMedGoogle Scholar
  43. Zollinger DR, Baalman KL, Rasband MN. The ins and outs of polarized axonal domains. Annu Rev Cell Dev Biol. 2015;31(1):647–67.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Cellular and Molecular Biology, Faculty of Biological SciencesPontificia Universidad Católica de ChileSantiagoChile
  2. 2.Department of Neuroscience and Biomedical Neuroscience Institute, Faculty of MedicineUniversidad de ChileSantiagoChile