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  • Review Article
  • Published:

Making protein interactions druggable: targeting PDZ domains

Nature Reviews Drug Discovery volume 3, pages 1047–1056 (2004)Cite this article

Key Points

  • PDZ domains are involved in the recruitment and interaction of proteins, and aid the formation of protein scaffolds and signalling networks. This is achieved by sequence-specific binding between a PDZ domain in one protein and a PDZ motif in another protein.

  • Targeting the PDZ domain of proteins with peptides or small molecules is therefore of interest as a way to interfere with protein interactions in disease. PICK1, a ubiquitous protein that contains a PDZ domain, is used as an example to discuss approaches, inherent challenges and outstanding questions relating to drug discovery for these targets.

  • PICK1 was first reported to interact with protein kinase C, and has since been implicated in the regulation of a variety of proteins involved in normal physiological processes, such as synaptic transmission and plasticity, sound stimulation and neuropathic pain sensitization. PICK1 is also putatively involved in neurodegenerative and neurological diseases, such as stroke and schizophrenia, and is also now being implicated in cancer.

  • One advantage of targeting PDZ domains is the potential to design drugs that are specific for a particular PDZ interaction. The most well-established method of interfering with PDZ interactions is the use of blocking peptides specific to the PDZ domain sequence. These serve as tools for studying the role of PDZ in protein interactions, but also have potential as therapeutics if issues such as peptide delivery and degradation can be overcome.

  • The development of small molecules that bind directly to PDZ domains or allosterically induce conformational change that hides the PDZ domain is desirable. Progress in this field has been limited but should now improve through the mapping of PDZ domains and the availability of X-ray crystallography data

  • A significant challenge in this field is to delineate the complex protein networks that PDZ domains are involved in. It is possible that certain PDZ interactions only occur in particular cell-specific contexts or stages of development, providing an opportunity for differential regulation. PDZ knockout models will continue to shed some light on this concept.

Abstract

Modulating protein–protein interactions involved in disease pathways is an attractive strategy for developing drugs, but remains a challenge to achieve. One approach is to target certain domains within proteins that mediate these interactions. One example of such a domain is the PDZ domain, which is involved in interactions between many different proteins in a variety of cellular contexts. Because PDZ domains have well-defined binding sites, they are promising targets for drug discovery. However, there is still much to learn about the function of these domains before drugs targeting PDZ interactions can become a reality.

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Figure 1: Structural domains of PICK1.
Figure 2: Modulating receptors by targeting PDZ domains.
Figure 3: Residues used in PDZ domain and motif interactions.

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References

  1. Arkin, M. R. & Wells, J. A. Small-molecule inhibitors of protein–protein interactions: progressing towards the dream. Nature Rev. Drug Discov. 3, 301–317 (2004).

    Article  CAS  Google Scholar 

  2. Berg, T. Modulation of protein–protein interactions with small organic molecules. Angew. Chem. Int. Ed. Engl. 42, 2462–2481 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Fischer, P. M. & Lane, P. L. Small-molecule inhibitors of the p53 suppressor HDM2: have protein–protein interactions come of age as drug targets? Trends Pharmacol. Sci. 25, 343–346 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Ponting, C. P. et al. PDZ domains: targeting signalling molecules to submembranous sites. Bioessays 19, 469–479 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 10, 771–781 (2004).

    Article  CAS  Google Scholar 

  6. Fanning, A. S. & Anderson, J. M. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J. Clin. Invest. 103, 767–772 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nourry, C., Grant, S. G. & Borg, J. P. PDZ domain proteins: plug and play! Sci. STKE 179, RE7 (2003).

    Google Scholar 

  8. Collingridge, G. L. & Isaac, J. T. Functional roles of protein interactions with AMPA and kainate receptors. Neurosci. Res. 47, 3–15 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Henley, J. M. Protein interactions implicated in AMPA receptor trafficking: a clear destination and an improving route map. Neurosci. Res. 45, 243–254 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cho, K. -O. et al. The rat brain postsynaptic density fraction contains a homolog of the Drosophila discslarge tumor suppressor protein. Neuron 9, 929–942 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Woods, D. F. & Bryant, P. J. The discs–large tumor suppressor gene of Drosophila encodes a guanylate kinase homolog localized at septate junctions. Cell 66, 451–464 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Itoh, M. et al. The 220-kD protein colocalizing with cadherins in non-epithelial cells is identical to ZO-1, a tight junction-associated protein in epithelial cells: cDNA cloning and immunoelectron microscopy. J. Cell Biol. 121, 491–502 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Hillier, B. J. et al. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS–syntrophin complex. Science 284, 812–815 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Songyang, Z. et al. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275, 73–77 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Staudinger, J. et al. PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system. J. Cell Biol. 128, 263–271 (1995). First paper to report the isolation and identification of PICK1 as a protein interacting with PKCα.

    Article  CAS  PubMed  Google Scholar 

  16. Staudinger, J. et al. Specific interaction of the PDZ domain protein PICK1 with the COOH terminus of protein kinase C-α. J. Biol. Chem. 272, 32019–32024 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Dev, K. K. et al. The protein kinase C α binding protein PICK1 interacts with short but not long form alternative splice variants of AMPA receptor subunits. Neuropharmacology 38, 635–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Xia, J. et al. Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1. Neuron 22, 179–187 (1999). Together with reference 17, this first reports that PICK1 interacts with the AMPA receptor subunit Glu 2.

    Article  CAS  PubMed  Google Scholar 

  19. Boudin, H. et al. Presynaptic clustering of mGluR7a requires the PICK1 PDZ domain binding site. Neuron 28, 485–497 (2000). Together with references 35 and 36, simultaneously reported the interaction between PICK1 and mGlu 7.

    Article  CAS  PubMed  Google Scholar 

  20. Boudin, H. & Craig, A. M. Molecular determinants for PICK1 synaptic aggregation and mGluR7a receptor coclustering: role of the PDZ, coiled-coil, and acidic domains. J. Biol. Chem. 276, 30270–30276 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Hanley, J. G. et al. NSF ATPase and α-/β-SNAPs disassemble the AMPA receptor-PICK1 complex. Neuron 34, 53–67 (2002). The authors provide the first description of an interaction between PICK1 and SNAP.

    Article  CAS  PubMed  Google Scholar 

  22. Takeya, R. et al. Interaction of the PDZ domain of human PICK1 with class I ADP-ribosylation factors. Biochem. Biophys. Res. Commun. 267, 149–155 (2000). Demonstrates that PICK1 interacts with ARFs.

    Article  CAS  PubMed  Google Scholar 

  23. Peter, B. J. et al. BAR Domains as sensors of membrane curvature: the amphiphysin BAR structure. Science 302, 495–499 (2004).

    Article  CAS  Google Scholar 

  24. Tarricone, C. et al. The structural basis of Arfaptin mediated cross-talk between Rac and Arf signalling pathways. Nature 411, 215–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Perez, J. L. et al. PICK1 targets activated protein kinase Cα to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J. Neurosci. 21, 5417–5428 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, W. L. et al. PICK1: an anchoring protein that specifically targets PKCα to mitochondria selectivity upon serum stimulation in NIH 3T3 cells. J. Biol. Chem. 278, 37705–37712 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Lin, W. J. et al. Mitogen-stimulated TIS21 protein interacts with a protein-kinase-Cα-binding protein rPICK1. Biochem. J. 354, 635–643 (2001). First report of a PICK1 interaction with TIS21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jourdi, H. et al. Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons. Dev. Biol. 263, 216–230 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kim, A. R. et al. Phosphorylation of 46-kDa protein of synaptic vesicle membranes is stimulated by GTP and Ca2+/calmodulin. Exp. Mol. Med. 34, 434–443 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Dev, K. K. et al. Regulation of mGlu(7) receptors by proteins that interact with the intracellular C-terminus. Trends Pharmacol. Sci. 22, 355–361 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Meyer, G, The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology 47, 724–733 (2004). Provides evidence of an interaction between PICK1 and neuroligin.

    Article  CAS  PubMed  Google Scholar 

  32. Hirbec, H. et al. The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs. J. Biol. Chem. 277, 15221–15224 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Barnes, G. N. & Slevin, J. T. Ionotrpoic glutamate receptor biology: effect on synaptic connectivity and function in neurological disease. Curr. Med. Chem. 10, 2059–2072 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Hirbec, H. et al. Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP. Neuron 37, 625–638 (2003). An interaction between PICK1 and kainate receptors is described.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dev, K. K. et al. PICK1 interacts with and regulates PKC phosphorylation of mGluR7. J. Neurosci. 20, 7252–7257 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. El Far, O. et al. Interaction of the C-terminal tail region of the metabotropic glutamate receptor 7 with the protein kinase C substrate PICK1. Eur. J. Neurosci. 12, 4215–4221 (2000).

    CAS  PubMed  Google Scholar 

  37. Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Srivastava, S. et al. Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21, 581–591 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Enz, R. & Croci, C. Different binding motifs in the metabotropic glutamate receptor type 7b for Filamin-A, PP1C, PICK1 and Syntenin allow the formation of multimeric protein complexes. Biochem. J. 372, 183–191 (2003). PICK1 suggested interaction between syntenin and PICK1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Perroy, J. et al. PICK1 is required for the control of synaptic transmission by the metabotropic glutamate receptor 7. EMBO J. 21, 2990–2999 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stowell, J. N. & Craig, A. M. Axon/dendrite targeting of metabotropic glutamate receptors by their cytoplasmic carboxy-terminal domains. Neuron 22, 525–536 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. McInvale, A. C. et al. Immunolocalization of PICK1 in the ascending auditory pathways of the adult rat. J. Comp. Neurol. 450, 382–394 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Garry, E. M. et al. Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit. Mol. Cell. Neurosci. 24, 10–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Himanen, J. P. & Nikolov, D. B. Eph signaling: a structural view. Trends Neurosci. 26, 46–51 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Torres, R. et al. PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453–1463 (1998). Eph receptors were the first receptors found to interact with PICK.

    Article  CAS  PubMed  Google Scholar 

  46. Cowen, C. A. et al. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 26, 417–430 (2000). The first interaction of PICK1 aquaporins and anion exchangers is described here.

    Article  Google Scholar 

  47. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho–GEF kalirin. Neuron 37, 263–274 (2003). PICK1 is suggested to interact with Kalirin and is linked to EphB receptors.

    Article  CAS  PubMed  Google Scholar 

  48. Williams, M. E. et al. Surface expression of the netrin receptor UNC5H1 is regulated through a protein kinase C-interacting protein/protein kinase-dependent mechanism. J. Neurosci. 23, 11279–11288 (2003). The interaction between UNC5H and PICK1 is first described.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Julin-Bastard, F. et al. The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins. J. Biol. Chem. 276, 15256–15263 (2001). First report of an interaction between PICK1 and ErbB2/HER2.

    Article  Google Scholar 

  50. Dziedzic, B. et al. Neuron-to-glia signaling mediated by excitatory amino acid receptors regulates ErbB receptor function in astroglial cells of the neuroendocrine brain. J. Neurosci. 23, 915–926 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Excoffon, K. J. A role for the PDZ-binding domain of the coxsackie B virus and adenovirus receptor (CAR) in cell adhesion and growth. J. Cell Sci. 117, 4401–4409 (2004). The authors demonstrate that PICK1 interacts with CAR.

    Article  CAS  PubMed  Google Scholar 

  52. Klapper, L. N. et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv. Cancer Res. 77, 25–79 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Torres, G. E. et al. Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30, 121–134 (2001). Evidence that PICK1 interacts with monoamine transporters.

    Article  CAS  PubMed  Google Scholar 

  54. Gainetdinov, R. R. & Caron, M. G. Monoamine transporters: from genes to behavior. Annu. Rev. Pharmacol. Toxicol. 43, 261–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Torres, G. E. et al. Plasma membrane monoamine transporters: structure, regulation and function. Nature Rev. Neurosci. 4, 13–25 (2003).

    Article  CAS  Google Scholar 

  56. Bengel, D. et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3,4-methylenedioxymeth-amphetamine ('Ecstasy') in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649–655 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Giros, B. et al. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–712 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Xu, F. et al. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nature Neurosci. 3, 465–471 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Bjerggaard, C. Surface targeting of the dopamine transporter involves discrete epitopes in the distal C terminus but does not require canonical PDZ domain interactions. J. Neurosci. 24, 7024–7036 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hong, C. J. Association study of PICK1 rs3952 polymorphism and schizophrenia. Neuroreport 15, 1965–1967 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Leonard, A. S. et al. cAMP-dependent protein kinase phosphorylation of the acid-sensing ion channel-1 regulates its binding to the protein interacting with C-kinase-1. Proc. Natl Acad. Sci. 100, 2029–2034 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duggan, A. et al. The PDZ domain protein PICK1 and the sodium channel BNaC1 interact and localize at mechanosensory terminals of dorsal root ganglion neurons and dendrites of central neurons. J. Biol. Chem. 277, 5203–5208 (2002). This paper together with ref 63 and 64 first revealed the interaction between PICK1 and BNaC channels.

    Article  CAS  PubMed  Google Scholar 

  63. Hruska-Hageman, A. M. et al. Interaction of the synaptic protein PICK1 (protein interacting with C kinase 1) with the non-voltage gated sodium channels BNC1 (brain Na+ channel 1) and ASIC (acid-sensing ion channel). Biochem. J. 361, 443–450 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Baron, A. et al. Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. J. Biol. Chem. 277, 50463–50468 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Deval, E. et al. ASIC2b-dependent regulation of ASIC3, an essential acid-sensing ion channel subunit in sensory neurons via the partner protein PICK-1. J. Biol. Chem. 279, 19531–19539 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Ferro, E. S. et al. Intracellullar peptides as putative natural regulators of protein interactions. J. Neurochem. (in the press).

  67. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Li, P. et al. AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nature Neurosci. 2, 972–977 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Xia, J. et al. Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron 28, 499–510 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Chung, H. J. et al. Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J. Neurosci. 20, 7258–7267 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim, C. H. et al. Interaction of the AMPA receptor subunit GluR2/3 with PDZ domains regulates hippocampal long-term depression. Proc. Natl Acad. Sci. USA 98, 11725–11730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chung, H. J. et al. Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300, 1751–1755 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Matsuda, S. et al. Phosphorylation of serine-880 in GluR2 by protein kinase C prevents its C terminus from binding with glutamate receptor-interacting protein. J. Neurochem. 73, 1765–1768 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Lin, S. H. et al. The carboxyl terminus of the prolactin-releasing peptide receptor interacts with PDZ domain proteins involved in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor clustering. Mol. Pharmacol. 60, 916–923 (2001). These authors were first to show that PICK1 can interact with PrRP receptors.

    Article  CAS  PubMed  Google Scholar 

  76. Terashima, A. et al. Regulation of synaptic strength and AMPA receptor subunit composition by PICK1. J. Neurosci. 24, 5381–5390 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nagai, Y. et al. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum. Mol. Genet. 12, 1253–1259 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. El-Agnaf, O. M. et al. A strategy for designing inhibitors of α-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB J. 18, 1315–1317 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Pawson, T. & Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Schlessinger, J. & Lemmon, M. A. SH2 and PTB domains in tyrosine kinase signaling. Sci. STKE 191, RE12 (2003).

    Google Scholar 

  81. Lemmon, M. A. Phosphoinositide recognition domains. Traffic 4, 201–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Joliot, A. & Prochiantz, A. Transduction peptides: from technology to physiology. Nature Cell Biol. 6, 189–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Iwakura, Y. et al. N-methyl-D-aspartate-induced α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor down-regulation involves interaction of the carboxyl terminus of GluR2/3 with Pick1. Ligand-binding studies using Sindbis vectors carrying AMPA receptor decoys. J. Biol. Chem. 276, 40025–40032 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Ehrengruber, M. U. et al. Gene transfer into neurons from hippocampal slices: comparison of recombinant Semliki Forest virus, adenovirus, adeno-associated virus, lentivirus, and measles virus. Mol. Cell. Neurosci. 17, 855–871 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Morris, M. C. et al. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nature Biotechnol. 19, 1173–1176 (2001).

    Article  CAS  Google Scholar 

  86. Aarts, M. et al. Treatment of ischemic brain damage by perturbing NMDA receptor–PSD-95 protein interactions. Science 298, 846–850 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Fujii, N. et al. A selective irreversible inhibitor targeting a PDZ protein interaction domain. J. Am. Chem. Soc. 125, 12074–12075 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Harris, B. Z. et al. Role of electrostatic interactions in PDZ domain ligand recognition. Biochemistry 42, 2797–2805 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Laboto, M. N. & Rabbitts, T. H. Intracellular antibodies and challenges facing their use as therapeutic agents. Trends Mol. Med. 9, 390–396 (2003).

    Article  CAS  Google Scholar 

  90. Clayton, J. The silent treatment. Nature 431, 599–605 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Shi, S. et al. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Migaud, M. et al. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396, 433–439 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Komiyama, N. H. et al. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. J. Neurosci. 22, 9721–9732 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bezprozvanny, I. & Maximov, A. Classification of PDZ domains. FEBS Lett. 509, 457–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Daniels, D. L. et al. Crystal structure of the hCASK PDZ domain reveals the structural basis of class II PDZ domain target recognition. Nature Struct. Biol. 5, 317–325 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Toogood, P. L. Inhibition of protein–protein association by small molecules: approaches and progress. J. Med. Chem. 45, 1543–1558 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Osten, P. et al. Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron 27, 313–325 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Dev, K. K. et al. The PDZ domain of PICK1 differentially accepts protein kinase C-α and GluR2 as interacting ligands. J. Biol. Chem. 279, 41393–41397 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Novak, K. A. P. et al. Investigation of the PDZ domain ligand binding site using chemically modified peptides. Bioorg. Med. Chem. Lett. 12, 2471–2474 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Zhang, M. & Wang, W. Organization of signaling complexes by PDZ-domain scaffold proteins. Acc. Chem. Res. 36, 530–538 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Ferrer, M. et al. A PDZ domain-based detection system for enzymatic assays. Anal. Biochem. 301, 207–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Burette, A. et al. Differential cellular and subcellular localization of the AMPA receptor-binding protein and glutamate receptor-interacting protein. J. Neurosci. 21, 495–503 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wyszynski, M. et al. Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo. J. Neurosci. 19, 6528–6537 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Beneyto, M. & Meador-Woodruff, J. H. Expression of transcripts encoding AMPA receptor subunits and associated postsynaptic proteins in the macaque brain. J. Comp. Neurol. 468, 530–554 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Passafaro, M. et al. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nature Neurosci. 4, 917–926 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Boeda, B. Myosin, VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 21, 6689–6699 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bladt, F. Epidermolysis bullosa and embryonic lethality in mice lacking the multi-PDZ domain protein GRIP1. Proc. Natl Acad. Sci. USA 99, 6816–6821 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I am grateful to J. F. Cryan for critical reading of this review. I wish to thank S. Manghani for help with artwork. My thanks to R. Kuhn and D. Hoyer for continued support.

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  1. Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, WSJ-386.7.43, Basel, CH-4002, Switzerland

    Kumlesh K. Dev

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DATABASES

Entrez Gene

Amyloid precursor protein

ASIC

BDNF

BNaC1

DAT

DlgA

Fe65

GluK5

harmonin

mGlu2

mGlu7

NSF

PKCα

PICK1

PSD95

PTEN

X11

ZO1

OMIM

Alzheimer's disease

Huntington's disease

Parkinson's disease

Glossary

COILED-COIL MOTIF

A protein structural domain that mediates subunit oligomerization. Coiled coils contain between two and five helices that twist around each other to form a supercoil.

SPINE-LIKE STRUCTURES

A particular morphology of a dendritic structure. It is a morphological extension from the dendrite that has a long shaft and a mushroom-like head.

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Dev, K. Making protein interactions druggable: targeting PDZ domains. Nat Rev Drug Discov 3, 1047–1056 (2004). https://doi.org/10.1038/nrd1578

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