Journal articles: 'PDZ domain proteins'

1

Ye, Fei, and Mingjie Zhang. "Structures and target recognition modes of PDZ domains: recurring themes and emerging pictures." Biochemical Journal 455, no. 1 (September 13, 2013): 1–14. http://dx.doi.org/10.1042/bj20130783.

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PDZ domains are highly abundant protein–protein interaction modules and are often found in multidomain scaffold proteins. PDZ-domain-containing scaffold proteins regulate multiple biological processes, including trafficking and clustering receptors and ion channels at defined membrane regions, organizing and targeting signalling complexes at specific cellular compartments, interfacing cytoskeletal structures with membranes, and maintaining various cellular structures. PDZ domains, each with ~90-amino-acid residues folding into a highly similar structure, are best known to bind to short C-terminal tail peptides of their target proteins. A series of recent studies have revealed that, in addition to the canonical target-binding mode, many PDZ–target interactions involve amino acid residues beyond the regular PDZ domain fold, which we refer to as extensions. Such extension sequences often form an integral structural and functional unit with the attached PDZ domain, which is defined as a PDZ supramodule. Correspondingly, PDZ-domain-binding sequences from target proteins are frequently found to require extension sequences beyond canonical short C-terminal tail peptides. Formation of PDZ supramodules not only affords necessary binding specificities and affinities demanded by physiological functions of PDZ domain targets, but also provides regulatory switches to be built in the PDZ–target interactions. At the 20th anniversary of the discovery of PDZ domain proteins, we try to summarize structural features and target-binding properties of such PDZ supramodules emerging from studies in recent years.

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Kim, Eunjoon, and Morgan Sheng. "PDZ domain proteins of synapses." Nature Reviews Neuroscience 5, no. 10 (October 2004): 771–81. http://dx.doi.org/10.1038/nrn1517.

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Hata, Yutaka, Hiroyuki Nakanishi, and Yoshimi Takai. "Synaptic PDZ domain-containing proteins." Neuroscience Research 32, no. 1 (September 1998): 1–7. http://dx.doi.org/10.1016/s0168-0102(98)00069-8.

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Subbaiah, Vanitha Krishna, Christian Kranjec, Miranda Thomas, and Lawrence Banks. "PDZ domains: the building blocks regulating tumorigenesis." Biochemical Journal 439, no. 2 (September 28, 2011): 195–205. http://dx.doi.org/10.1042/bj20110903.

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Over 250 PDZ (PSD95/Dlg/ZO-1) domain-containing proteins have been described in the human proteome. As many of these possess multiple PDZ domains, the potential combinations of associations with proteins that possess PBMs (PDZ-binding motifs) are vast. However, PDZ domain recognition is a highly specific process, and much less promiscuous than originally thought. Furthermore, a large number of PDZ domain-containing proteins have been linked directly to the control of processes whose loss, or inappropriate activation, contribute to the development of human malignancies. These regulate processes as diverse as cytoskeletal organization, cell polarity, cell proliferation and many signal transduction pathways. In the present review, we discuss how PBM–PDZ recognition and imbalances therein can perturb cellular homoeostasis and ultimately contribute to malignant progression.

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te Velthuis, Aartjan J. W., and Christoph P. Bagowski. "PDZ and LIM Domain-Encoding Genes: Molecular Interactions and their Role in Development." Scientific World JOURNAL 7 (2007): 1470–92. http://dx.doi.org/10.1100/tsw.2007.232.

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PDZ/LIM genes encode a group of proteins that play very important, but diverse, biological roles. They have been implicated in numerous vital processes, e.g., cytoskeleton organization, neuronal signaling, cell lineage specification, organ development, and oncogenesis.In mammals, there are ten genes that encode for both a PDZ domain, and one or several LIM domains: four genes of the ALP subfamily (ALP, Elfin, Mystique, and RIL), three of the Enigma subfamily (Enigma, Enigma Homolog, and ZASP), the two LIM kinases (LIMK1 and LIMK2), and the LIM only protein 7 (LMO7). Functionally, all PDZ and LIM domain proteins share an important trait, i.e., they can associate with and/or influence the actin cytoskeleton.We review here the PDZ and LIM domain—encoding genes and their different gene structures, their binding partners, and their role in development and disease. Emphasis is laid on the important questions: why the combination of a PDZ domain with one or more LIM domains is found in such a diverse group of proteins, and what role the PDZ/LIM module could have in signaling complex assembly and localization.Furthermore, the current knowledge on splice form specific expression and the function of these alternative transcripts during vertebrate development will be discussed, since another source of complexity for the PDZ and LIM domain—encoding proteins is introduced by alternative splicing, which often creates different domain combinations.

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Singh, Varsha, Jianbo Yang, Boyoung Cha, Tiane-e. Chen, Rafiquel Sarker, Jianyi Yin, Leela Rani Avula, Ming Tse, and Mark Donowitz. "Sorting nexin 27 regulates basal and stimulated brush border trafficking of NHE3." Molecular Biology of the Cell 26, no. 11 (June 2015): 2030–43. http://dx.doi.org/10.1091/mbc.e14-12-1597.

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Sorting nexin 27 (SNX27) contains a PDZ domain that is phylogenetically related to the PDZ domains of the NHERF proteins. Studies on nonepithelial cells have shown that this protein is located in endosomes, where it regulates trafficking of cargo proteins in a PDZ domain–dependent manner. However, the role of SNX27 in trafficking of cargo proteins in epithelial cells has not been adequately explored. Here we show that SNX27 directly interacts with NHE3 (C-terminus) primarily through the SNX27 PDZ domain. A combination of knockdown and reconstitution experiments with wild type and a PDZ domain mutant (GYGF → GAGA) of SNX27 demonstrate that the PDZ domain of SNX27 is required to maintain basal NHE3 activity and surface expression of NHE3 in polarized epithelial cells. Biotinylation-based recycling and degradation studies in intestinal epithelial cells show that SNX27 is required for the exocytosis (not endocytosis) of NHE3 from early endosome to plasma membrane. SNX27 is also required to regulate the retention of NHE3 on the plasma membrane. The findings of the present study extend our understanding of PDZ-mediated recycling of cargo proteins from endosome to plasma membrane in epithelial cells.

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Guy, Pamela M., Daryn A. Kenny, and Gordon N. Gill. "The PDZ Domain of the LIM Protein Enigma Binds to β-Tropomyosin." Molecular Biology of the Cell 10, no. 6 (June 1999): 1973–84. http://dx.doi.org/10.1091/mbc.10.6.1973.

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PDZ and LIM domains are modular protein interaction motifs present in proteins with diverse functions. Enigma is representative of a family of proteins composed of a series of conserved PDZ and LIM domains. The LIM domains of Enigma and its most related family member, Enigma homology protein, bind to protein kinases, whereas the PDZ domains of Enigma and family member actin-associated LIM protein bind to actin filaments. Enigma localizes to actin filaments in fibroblasts via its PDZ domain, and actin-associated LIM protein binds to and colocalizes with the actin-binding protein α-actinin-2 at Z lines in skeletal muscle. We show that Enigma is present at the Z line in skeletal muscle and that the PDZ domain of Enigma binds to a skeletal muscle target, the actin-binding protein tropomyosin (skeletal β-TM). The interaction between Enigma and skeletal β-TM was specific for the PDZ domain of Enigma, was abolished by mutations in the PDZ domain, and required the PDZ-binding consensus sequence (Thr-Ser-Leu) at the extreme carboxyl terminus of skeletal β-TM. Enigma interacted with isoforms of tropomyosin expressed in C2C12 myotubes and formed an immunoprecipitable complex with skeletal β-TM in transfected cells. The association of Enigma with skeletal β-TM suggests a role for Enigma as an adapter protein that directs LIM-binding proteins to actin filaments of muscle cells.

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Nourry, C., S. G. N. Grant, and J. P. Borg. "PDZ Domain Proteins: Plug and Play!" Science Signaling 2003, no. 179 (April 22, 2003): re7. http://dx.doi.org/10.1126/stke.2003.179.re7.

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9

Marfatia, S. M., J. H. Morais Cabral, L. Lin, C. Hough, P. J. Bryant, L. Stolz, and A. H. Chishti. "Modular organization of the PDZ domains in the human discs-large protein suggests a mechanism for coupling PDZ domain-binding proteins to ATP and the membrane cytoskeleton." Journal of Cell Biology 135, no. 3 (November 1, 1996): 753–66. http://dx.doi.org/10.1083/jcb.135.3.753.

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The human homologue (hDIg) of the Drosophila discs-large tumor suppressor (DIg) is a multidomain protein consisting of a carboxyl-terminal guanylate kinase-like domain, an SH3 domain, and three slightly divergent copies of the PDZ (DHR/GLGF) domain. Here have examined the structural organization of the three PDZ domains of hDIg using a combination of protease digestion and in vitro binding measurements. Our results show that the PDZ domains are organized into two conformationally stable modules one (PDZ, consisting of PDZ domains 1 and 2, and the other (PDZ) corresponding to the third PDZ domain. Using amino acid sequencing and mass spectrometry, we determined the boundaries of the PDZ domains after digestion with endoproteinase Asp-N, trypsin, and alpha-chymotrypsin. The purified PDZ1+2, but not the PDZ3 domain, contains a high affinity binding site for the cytoplasmic domain of Shaker-type K+ channels. Similarly, we demonstrate that the PDZ1+2 domain can also specifically bind to ATP. Furthermore, we provide evidence for an in vivo interaction between hDIg and protein 4.1 and show that the hDIg protein contains a single high affinity protein 4.1-binding site that is not located within the PDZ domains. The results suggest a mechanism by which PDZ domain-binding proteins may be coupled to ATP and the membrane cytoskeleton via hDlg.

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Wu, Jiawen, Yinshan Yang, Jiahai Zhang, Peng Ji, Wenjing Du, Peng Jiang, Dinghai Xie, et al. "Domain-swapped Dimerization of the Second PDZ Domain of ZO2 May Provide a Structural Basis for the Polymerization of Claudins." Journal of Biological Chemistry 282, no. 49 (September 25, 2007): 35988–99. http://dx.doi.org/10.1074/jbc.m703826200.

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Zonula occludens proteins (ZOs), including ZO1/2/3, are tight junction-associated proteins. Each of them contains three PDZ domains. It has been demonstrated that ZO1 can form either homodimers or heterodimers with ZO2 or ZO3 through the second PDZ domain. However, the underlying structural basis is not well understood. In this study, the solution structure of the second PDZ domain of ZO2 (ZO2-PDZ2) was determined using NMR spectroscopy. The results revealed a novel dimerization mode for PDZ domains via three-dimensional domain swapping, which can be generalized to homodimers of ZO1-PDZ2 or ZO3-PDZ2 and heterodimers of ZO1-PDZ2/ZO2-PDZ2 or ZO1-PDZ2/ZO3-PDZ2 due to high conservation between PDZ2 domains in ZO proteins. Furthermore, GST pulldown experiments and immunoprecipitation studies demonstrated that interactions between ZO1-PDZ2 and ZO2-PDZ2 and their self-associations indeed exist both in vitro and in vivo. Chemical cross-linking and dynamic laser light scattering experiments revealed that both ZO1-PDZ2 and ZO2-PDZ2 can form oligomers in solution. This PDZ domain-mediated oligomerization of ZOs may provide a structural basis for the polymerization of claudins, namely the formation of tight junctions.

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11

Sheng, M., and E. Kim. "The Shank family of scaffold proteins." Journal of Cell Science 113, no. 11 (June 1, 2000): 1851–56. http://dx.doi.org/10.1242/jcs.113.11.1851.

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Shank proteins make up a new family of scaffold proteins recently identified through their interaction with a variety of membrane and cytoplasmic proteins. Shank polypeptides contain multiple sites for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PDZ domain, a long proline-rich region, and a SAM domain. Binding partners for most of these domains have been identified: for instance, the PDZ domain of Shank proteins interacts with GKAP (a postsynaptic-density protein) as well as several G-protein-coupled receptors. The specific localization of Shank proteins at postsynaptic sites of brain excitatory synapses suggests a role for this family of proteins in the organization of cytoskeletal/ signaling complexes at specialized cell junctions.

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12

Korb, Doreen, Priscilla Y. Tng, Vladimir M. Milenkovic, Nadine Reichhart, Olaf Strauss, Oliver Ritter, Tobias Fischer, Peter M. Benz, and Kai Schuh. "Identification of PDZ Domain Containing Proteins Interacting with 1.2 and PMCA4b." ISRN Cell Biology 2013 (February 7, 2013): 1–16. http://dx.doi.org/10.1155/2013/265182.

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PDZ (PSD-95/Disc large/Zonula occludens-1) protein interaction domains bind to cytoplasmic protein C-termini of transmembrane proteins. In order to identify new interaction partners of the voltage-gated L-type Ca2+ channel 1.2 and the plasma membrane Ca2+ ATPase 4b (PMCA4b), we used PDZ domain arrays probing for 124 PDZ domains. We confirmed this by GST pull-downs and immunoprecipitations. In PDZ arrays, strongest interactions with 1.2 and PMCA4b were found for the PDZ domains of SAP-102, MAST-205, MAGI-1, MAGI-2, MAGI-3, and ZO-1. We observed binding of the 1.2 C-terminus to PDZ domains of NHERF1/2, Mint-2, and CASK. PMCA4b was observed to interact with Mint-2 and its known interactions with Chapsyn-110 and CASK were confirmed. Furthermore, we validated interaction of 1.2 and PMCA4b with NHERF1/2, CASK, MAST-205 and MAGI-3 via immunoprecipitation. We also verified the interaction of 1.2 and nNOS and hypothesized that nNOS overexpression might reduce Ca2+ influx through 1.2. To address this, we measured Ca2+ currents in HEK 293 cells co-expressing 1.2 and nNOS and observed reduced voltage-dependent 1.2 activation. Taken together, we conclude that 1.2 and PMCA4b bind promiscuously to various PDZ domains, and that our data provides the basis for further investigation of the physiological consequences of these interactions.

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Jo, Kiwon, Bart Rutten, Robert C. Bunn, and David S. Bredt. "Actinin-Associated LIM Protein-Deficient Mice Maintain Normal Development and Structure of Skeletal Muscle." Molecular and Cellular Biology 21, no. 5 (March 1, 2001): 1682–87. http://dx.doi.org/10.1128/mcb.21.5.1682-1687.2001.

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ABSTRACT The actinin-associated LIM protein, ALP, is the prototype of a large family of proteins containing an N-terminal PDZ domain and a C-terminal LIM domain. These PDZ-LIM proteins are components of the muscle cytoskeleton and occur along the Z lines owing to interaction of the PDZ domain with the spectrin-like repeats of α-actinin. Because PDZ and LIM domains are typically found in proteins that mediate cellular signaling, PDZ-LIM proteins are suspected to participate in muscle development. Interestingly the ALP gene occurs at 4q35 near the heterochromatic region mutated in facioscapulohumeral muscular dystrophy, indicating a possible role for ALP in this disease. Here, we describe the generation and analysis of mice lacking the ALP gene. Surprisingly, the ALP knockout mice show no gross histological abnormalities and maintain sarcolemmal integrity as determined by serum pyruvate kinase assays. The absence of a dystrophic phenotype in these mice suggests that down-regulation of ALP does not participate in facioscapulohumeral muscular dystrophy. These data suggest that ALP does not participate in muscle development or that an alternative PDZ-LIM protein can compensate for the lack of ALP.

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14

Brône, Bert, and Jan Eggermont. "PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes." American Journal of Physiology-Cell Physiology 288, no. 1 (January 2005): C20—C29. http://dx.doi.org/10.1152/ajpcell.00368.2004.

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PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am J Physiol Cell Physiol 288: C20–C29, 2005; doi:10.1152/ajpcell.00368.2004.—The plasma membrane of epithelial cells is subdivided into two physically separated compartments known as the apical and basolateral membranes. To obtain directional transepithelial solute transport, membrane transporters (i.e., ion channels, cotransporters, exchangers, and ion pumps) need to be targeted selectively to either of these membrane domains. In addition, the transport properties of an epithelial cell will be maintained only if these membrane transporters are retained and properly regulated in their specific membrane compartments. Recent reports have indicated that PDZ domain-containing proteins play a dual role in these processes and, in addition, that different apical and basolateral PDZ proteins perform similar tasks in their respective membrane domains. First, although PDZ-based interactions are dispensable for the biosynthetic targeting to the proper membrane domain, the PDZ network ensures that the membrane proteins are efficiently retained at the cell surface. Second, the close spatial positioning of functionally related proteins (e.g., receptors, kinases, channels) into a signal transduction complex (transducisome) allows fast and efficient control of membrane transport processes.

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15

Fan, Jing-Song, and Mingjie Zhang. "Signaling Complex Organization by PDZ Domain Proteins." Neurosignals 11, no. 6 (2002): 315–21. http://dx.doi.org/10.1159/000068256.

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Li, Zairong, Outhiriaradjou Benard, and Robert F. Margolskee. "Gγ13 Interacts with PDZ Domain-containing Proteins." Journal of Biological Chemistry 281, no. 16 (February 10, 2006): 11066–73. http://dx.doi.org/10.1074/jbc.m600113200.

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17

Ranganathan, Rama, and Elliott M. Ross. "PDZ domain proteins: Scaffolds for signaling complexes." Current Biology 7, no. 12 (December 1997): R770—R773. http://dx.doi.org/10.1016/s0960-9822(06)00401-5.

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Wofford, Haley A., Josh Myers-Dean, Brandon A. Vogel, Kevin Alexander Estrada Alamo, Frederick A. Longshore-Neate, Filip Jagodzinski, and Jeanine F. Amacher. "Domain Analysis and Motif Matcher (DAMM): A Program to Predict Selectivity Determinants in Monosiga brevicollis PDZ Domains Using Human PDZ Data." Molecules 26, no. 19 (October 5, 2021): 6034. http://dx.doi.org/10.3390/molecules26196034.

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Choanoflagellates are single-celled eukaryotes with complex signaling pathways. They are considered the closest non-metazoan ancestors to mammals and other metazoans and form multicellular-like states called rosettes. The choanoflagellate Monosiga brevicollis contains over 150 PDZ domains, an important peptide-binding domain in all three domains of life (Archaea, Bacteria, and Eukarya). Therefore, an understanding of PDZ domain signaling pathways in choanoflagellates may provide insight into the origins of multicellularity. PDZ domains recognize the C-terminus of target proteins and regulate signaling and trafficking pathways, as well as cellular adhesion. Here, we developed a computational software suite, Domain Analysis and Motif Matcher (DAMM), that analyzes peptide-binding cleft sequence identity as compared with human PDZ domains and that can be used in combination with literature searches of known human PDZ-interacting sequences to predict target specificity in choanoflagellate PDZ domains. We used this program, protein biochemistry, fluorescence polarization, and structural analyses to characterize the specificity of A9UPE9_MONBE, a M. brevicollis PDZ domain-containing protein with no homology to any metazoan protein, finding that its PDZ domain is most similar to those of the DLG family. We then identified two endogenous sequences that bind A9UPE9 PDZ with <100 μM affinity, a value commonly considered the threshold for cellular PDZ–peptide interactions. Taken together, this approach can be used to predict cellular targets of previously uncharacterized PDZ domains in choanoflagellates and other organisms. Our data contribute to investigations into choanoflagellate signaling and how it informs metazoan evolution.

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Reczek, David, and Anthony Bretscher. "Identification of Epi64, a Tbc/Rabgap Domain–Containing Microvillar Protein That Binds to the First PDZ Domain of Ebp50 and E3karp." Journal of Cell Biology 153, no. 1 (April 2, 2001): 191–206. http://dx.doi.org/10.1083/jcb.153.1.191.

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The cortical scaffolding proteins EBP50 (ERM-binding phosphoprotein-50) and E3KARP (NHE3 kinase A regulatory protein) contain two PDZ (PSD-95/DlgA/ZO-1–like) domains followed by a COOH-terminal sequence that binds to active ERM family members. Using affinity chromatography, we identified polypeptides from placental microvilli that bind the PDZ domains of EBP50. Among these are 64- and/or 65-kD differentially phosphorylated polypeptides that bind preferentially to the first PDZ domain of EBP50, as well as to E3KARP, and that we call EPI64 (EBP50–PDZ interactor of 64 kD). The gene for human EPI64 lies on chromosome 22 where nine exons specify a protein of 508 residues that contains a Tre/Bub2/Cdc16 (TBC)/rab GTPase-activating protein (GAP) domain. EPI64 terminates in DTYL, which is necessary for binding to the PDZ domains of EBP50, as a mutant ending in DTYLA no longer interacts. EPI64 colocalizes with EBP50 and ezrin in syncytiotrophoblast and cultured cell microvilli, and this localization in cultured cells is abolished by introduction of the DTYLA mutation. In addition to EPI64, immobilized EBP50 PDZ domains retain several polypeptides from placental microvilli, including an isoform of nadrin, a rhoGAP domain–containing protein implicated in regulating vesicular transport. Nadrin binds EBP50 directly, probably through its COOH-terminal STAL sequence. Thus, EBP50 appears to bind membrane proteins as well as factors potentially involved in regulating membrane traffic.

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20

Harris, Baruch Z., and Wendell A. Lim. "Mechanism and role of PDZ domains in signaling complex assembly." Journal of Cell Science 114, no. 18 (September 15, 2001): 3219–31. http://dx.doi.org/10.1242/jcs.114.18.3219.

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PDZ domains are protein-protein recognition modules that play a central role in organizing diverse cell signaling assemblies. These domains specifically recognize short C-terminal peptide motifs, but can also recognize internal sequences that structurally mimic a terminus. PDZ domains can therefore be used in combination to bind an array of target proteins or to oligomerize into branched networks. Several PDZ-domain-containing proteins play an important role in the transport, localization and assembly of supramolecular signaling complexes. Examples of such PDZ-mediated assemblies exist in Drosophila photoreceptor cells and at mammalian synapses. The predominance of PDZ domains in metazoans indicates that this highly specialized scaffolding module probably evolved in response to the increased signaling needs of multicellular organisms.

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Malmberg, Emily K., Thaher Pelaseyed, Åsa C. Petersson, Ursula E. Seidler, Hugo De Jonge, John R. Riordan, and Gunnar C. Hansson. "The C-terminus of the transmembrane mucin MUC17 binds to the scaffold protein PDZK1 that stably localizes it to the enterocyte apical membrane in the small intestine." Biochemical Journal 410, no. 2 (February 12, 2008): 283–89. http://dx.doi.org/10.1042/bj20071068.

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The membrane-bound mucins have a heavily O-glycosylated extracellular domain, a single-pass membrane domain and a short cytoplasmic tail. Three of the membrane-bound mucins, MUC3, MUC12 and MUC17, are clustered on chromosome 7 and found in the gastrointestinal tract. These mucins have C-terminal sequences typical of PDZ-domain-binding proteins. To identify PDZ proteins that are able to interact with the mucins, we screened PDZ domain arrays using YFP (yellow fluorescent protein)-tagged proteins. MUC17 exhibited a strong binding to PDZK1 (PDZ domain containing 1), whereas the binding to NHERF1 (Na+/H+-exchanger regulatory factor 1) was weak. Furthermore, we showed weak binding of MUC12 to PDZK1, NHERF1 and NHERF2. GST (glutathione transferase) pull-down experiments confirmed that the C-terminal tail of MUC17 co-precipitates with the scaffold protein PDZK1 as identified by MS. This was mediated through the C-terminal PDZ-interaction site in MUC17, which was capable of binding to three of the four PDZ domains in PDZK1. Immunostaining of wild-type or Pdzk1−/− mouse jejunum with an antiserum against Muc3(17), the mouse orthologue of human MUC17, revealed strong brush-border membrane staining in the wild-type mice compared with an intracellular Muc3(17) staining in the Pdzk1−/− mice. This suggests that Pdzk1 plays a specific role in stabilizing Muc3(17) in the apical membrane of small intestinal enterocytes.

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Murciano-Calles, Javier. "The Conformational Plasticity Vista of PDZ Domains." Life 10, no. 8 (July 27, 2020): 123. http://dx.doi.org/10.3390/life10080123.

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The PDZ domain (PSD95-Discs large-ZO1) is a widespread modular domain present in the living organisms. A prevalent function in the PDZ family is to serve as scaffolding and adaptor proteins connecting multiple partners in signaling pathways. An explanation of the flexible functionality in this domain family, based just on a static perspective of the structure–activity relationship, might fall short. More dynamic and conformational aspects in the protein fold can be the reasons for such functionality. Folding studies indeed showed an ample and malleable folding landscape for PDZ domains where multiple intermediate states were experimentally detected. Allosteric phenomena that resemble energetic coupling between residues have also been found in PDZ domains. Additionally, several PDZ domains are modulated by post-translational modifications, which introduce conformational switches that affect binding. Altogether, the ability to connect diverse partners might arise from the intrinsic plasticity of the PDZ fold.

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Xia, Houhui, Sara T. Winokur, Wen-Lin Kuo, Michael R. Altherr, and David S. Bredt. "Actinin-associated LIM Protein: Identification of a Domain Interaction between PDZ and Spectrin-like Repeat Motifs." Journal of Cell Biology 139, no. 2 (October 20, 1997): 507–15. http://dx.doi.org/10.1083/jcb.139.2.507.

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PDZ motifs are protein–protein interaction domains that often bind to COOH-terminal peptide sequences. The two PDZ proteins characterized in skeletal muscle, syntrophin and neuronal nitric oxide synthase, occur in the dystrophin complex, suggesting a role for PDZ proteins in muscular dystrophy. Here, we identify actinin-associated LIM protein (ALP), a novel protein in skeletal muscle that contains an NH2-terminal PDZ domain and a COOH-terminal LIM motif. ALP is expressed at high levels only in differentiated skeletal muscle, while an alternatively spliced form occurs at low levels in the heart. ALP is not a component of the dystrophin complex, but occurs in association with α-actinin-2 at the Z lines of myofibers. Biochemical and yeast two-hybrid analyses demonstrate that the PDZ domain of ALP binds to the spectrin-like motifs of α-actinin-2, defining a new mode for PDZ domain interactions. Fine genetic mapping studies demonstrate that ALP occurs on chromosome 4q35, near the heterochromatic locus that is mutated in fascioscapulohumeral muscular dystrophy.

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Morales, Fabiana C., Yoko Takahashi, Safan Momin, Henry Adams, Xiaomin Chen, and Maria-Magdalena Georgescu. "NHERF1/EBP50 Head-to-Tail Intramolecular Interaction Masks Association with PDZ Domain Ligands." Molecular and Cellular Biology 27, no. 7 (January 22, 2007): 2527–37. http://dx.doi.org/10.1128/mcb.01372-06.

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ABSTRACT Loss of cell polarity is one of the initial alterations in the development of human epithelial cancers. Na+/H+ exchanger regulatory factor (NHERF) homologous adaptors 1 and 2 are membrane-associated proteins composed of two amino (N)-terminal PDZ domains and an ezrin-radixin-moesin (ERM)-binding (EB) carboxyl (C)-terminal region. We describe here an intramolecular conformation of NHERF1/EBP50 (ERM-binding phosphoprotein 50) in which the C-terminal EB region binds to the PDZ2 domain. This novel head-to-tail conformation masked the interaction of both PDZ domains with PDZ domain-specific ligands, such as PTEN and β-catenin. An EB region composite structure comprising an α-helix ending in a PDZ-binding motif imparted opposite effects to NHERF1 associations, mediating binding to ERM proteins and inhibiting binding of PDZ domain ligands. The PDZ domain inhibition was released by prior association of ezrin with the EB region, a condition that occurs in vivo and likely disrupts NHERF1 head-to-tail interaction. In contrast, NHERF2 did not present a regulatory mechanism for protein complex formation. Functionally, NHERF1 is required to organize complexes at the apical membranes of polarized epithelial cells. The regulation of NHERF1 interactions at the apical membrane thus appears to be a dynamic process that is important for maintaining epithelial-tissue integrity.

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Gallo, Raffaella, Erika De Sensi, Francesca Storino, and Simona Panni. "An Unconventional Ligand for Scribble PDZ-4 Domain Mediates Its Interaction with Dusp26." BioChem 2, no. 1 (February 15, 2022): 83–92. http://dx.doi.org/10.3390/biochem2010006.

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PDZ domains are involved in many cellular processes and are key regulators of the cell physiology. A huge number of studies have investigated the binding specificity of PDZ domains to the carboxyl-terminal sequence of target proteins, while the molecular mechanisms that mediate the recognition of internal binding regions are largely unexplored. In the present study, we describe a ligand motif located in the catalytic domain of the phosphatase Dusp26 which mediates its binding to the PDZ-4 of Scribble. Site-directed mutagenesis identified a conserved tyrosine residue as relevant for the binding. The interaction with the PDZ domain could help the phosphatase to recruit its specific targets.

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Huesgen, Pitter F., Philipp Scholz, and Iwona Adamska. "The Serine Protease HhoA from Synechocystis sp. Strain PCC 6803: Substrate Specificity and Formation of a Hexameric Complex Are Regulated by the PDZ Domain." Journal of Bacteriology 189, no. 18 (July 6, 2007): 6611–18. http://dx.doi.org/10.1128/jb.00883-07.

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ABSTRACT Enzymes of the ATP-independent Deg serine endopeptidase family are very flexible with regard to their substrate specificity. Some family members cleave only one substrate, while others act as general proteases on unfolded substrates. The proteolytic activity of Deg proteases is regulated by PDZ protein interaction domains. Here we characterized the HhoA protease from Synechocystis sp. strain PCC 6803 in vitro using several recombinant protein constructs. The proteolytic activity of HhoA was found to increase with temperature and basic pH and was stimulated by the addition of Mg2+ or Ca2+. We found that the single PDZ domain of HhoA played a critical role in regulating protease activity and in the assembly of a hexameric complex. Deletion of the PDZ domain strongly reduced proteolysis of a sterically challenging resorufin-labeled casein substrate, but unlabeled β-casein was still degraded. Reconstitution of the purified HhoA with total membrane proteins isolated from Synechocystis sp. wild-type strain PCC 6803 and a ΔhhoA mutant resulted in specific degradation of selected proteins at elevated temperatures. We concluded that a single PDZ domain of HhoA plays a critical role in defining the protease activity and oligomerization state, combining the functions that are attributed to two PDZ domains in the homologous DegP protease from Escherichia coli. Based on this first enzymatic study of a Deg protease from cyanobacteria, we propose a general role for HhoA in the quality control of extracytoplasmic proteins, including membrane proteins, in Synechocystis sp. strain PCC 6803.

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Roh, Michael H., Olga Makarova, Chia-Jen Liu, Shin, Seonok Lee, Stephanie Laurinec, Meera Goyal, Roger Wiggins, and Ben Margolis. "The Maguk protein, Pals1, functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost." Journal of Cell Biology 157, no. 1 (April 1, 2002): 161–72. http://dx.doi.org/10.1083/jcb.200109010.

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Membrane-associated guanylate kinase (Maguk) proteins are scaffold proteins that contain PSD-95–Discs Large–zona occludens-1 (PDZ), Src homology 3, and guanylate kinase domains. A subset of Maguk proteins, such as mLin-2 and protein associated with Lin-7 (Pals)1, also contain two L27 domains: an L27C domain that binds mLin-7 and an L27N domain of unknown function. Here, we demonstrate that the L27N domain targets Pals1 to tight junctions by binding to a PDZ domain protein, Pals1-associated tight junction (PATJ) protein, via a unique Maguk recruitment domain. PATJ is a homologue of Drosophila Discs Lost, a protein that is crucial for epithelial polarity and that exists in a complex with the apical polarity determinant, Crumbs. PATJ and a human Crumbs homologue, CRB1, colocalize with Pals1 to tight junctions, and CRB1 interacts with PATJ albeit indirectly via binding the Pals1 PDZ domain. In agreement, we find that a Drosophila homologue of Pals1 participates in identical interactions with Drosophila Crumbs and Discs Lost. This Drosophila Pals1 homologue has been demonstrated recently to represent Stardust, a crucial polarity gene in Drosophila. Thus, our data identifies a new multiprotein complex that appears to be evolutionarily conserved and likely plays an important role in protein targeting and cell polarity.

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Caillet-Saguy, Célia, and Nicolas Wolff. "PDZ-Containing Proteins Targeted by the ACE2 Receptor." Viruses 13, no. 11 (November 15, 2021): 2281. http://dx.doi.org/10.3390/v13112281.

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Angiotensin-converting enzyme 2 (ACE2) is a main receptor for SARS-CoV-2 entry to the host cell. Indeed, the first step in viral entry is the binding of the viral trimeric spike (S) protein to ACE2. Abundantly present in human epithelial cells of many organs, ACE2 is also expressed in the human brain. ACE2 is a type I membrane protein with an extracellular N-terminal peptidase domain and a C-terminal collectrin-like domain that ends with a single transmembrane helix and an intracellular 44-residue segment. This C-terminal segment contains a PDZ-binding motif (PBM) targeting protein-interacting domains called PSD-95/Dlg/ZO-1 (PDZ). Here, we identified the human PDZ specificity profile of the ACE2 PBM using the high-throughput holdup assay and measuring the binding intensities of the PBM of ACE2 against the full human PDZome. We discovered 14 human PDZ binders of ACE2 showing significant binding with dissociation constants’ values ranging from 3 to 81 μM. NHERF, SHANK, and SNX27 proteins found in this study are involved in protein trafficking. The PDZ/PBM interactions with ACE2 could play a role in ACE2 internalization and recycling that could be of benefit for the virus entry. Interestingly, most of the ACE2 partners we identified are expressed in neuronal cells, such as SHANK and MAST families, and modifications of the interactions between ACE2 and these neuronal proteins may be involved in the neurological symptoms of COVID-19.

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Tao, Feng, Qiang Chen, Yuko Sato, John Skinner, Pei Tang, and Roger A. Johns. "Inhalational Anesthetics Disrupt Postsynaptic Density Protein-95, Drosophila Disc Large Tumor Suppressor, and Zonula Occludens-1 Domain Protein Interactions Critical to Action of Several Excitatory Receptor Channels Related to Anesthesia." Anesthesiology 122, no. 4 (April 1, 2015): 776–86. http://dx.doi.org/10.1097/aln.0000000000000609.

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Abstract Background: The authors have shown previously that inhaled anesthetics disrupt the interaction between the second postsynaptic density protein-95, Drosophila disc large tumor suppressor, and zonula occludens-1 (PDZ) domain of postsynaptic density protein-95 (PSD-95) and the C-terminus of N-methyl-d-aspartate receptor subunits NR2A and NR2B. The study data indicate that PDZ domains may serve as a molecular target for inhaled anesthetics. However, the underlying molecular mechanisms remain to be illustrated. Methods: Glutathione S-transferase pull-down assay, coimmunoprecipitation, and yeast two-hybrid analysis were used to assess PDZ domain–mediated protein–protein interactions in different conditions. Nuclear magnetic resonance spectroscopy was used to investigate isoflurane-induced chemical shift changes in the PDZ1–3 domains of PSD-95. A surface plasmon resonance–based BIAcore (Sweden) assay was used to examine the ability of isoflurane to inhibit the PDZ domain–mediated protein–protein interactions in real time. Results: Halothane and isoflurane dose-dependently inhibited PDZ domain–mediated interactions between PSD-95 and Shaker-type potassium channel Kv1.4 and between α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and its interacting proteins—glutamate receptor–interacting protein or protein interacting with c kinase 1. However, halothane and isoflurane had no effect on PDZ domain–mediated interactions between γ-aminobutyric acid type B receptor and its interacting proteins. The inhaled anesthetic isoflurane mostly affected the residues close to or in the peptide-binding groove of PSD-95 PDZ1 and PDZ2 (especially PDZ2), while barely affecting the peptide-binding groove of PSD-95 PDZ3. Conclusion: These results suggest that inhaled anesthetics interfere with PDZ domain–mediated protein–protein interactions at several receptors important to neuronal excitation, anesthesia, and pain processing.

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Jiang, Xinyuan, Zhiyong Xu, Sujing Jiang, Huan Wang, Mingshu Xiao, Yueli Shi, and Kai Wang. "PDZ and LIM Domain-Encoding Genes: Their Role in Cancer Development." Cancers 15, no. 20 (October 19, 2023): 5042. http://dx.doi.org/10.3390/cancers15205042.

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PDZ-LIM family proteins (PDLIMs) are a kind of scaffolding proteins that contain PDZ and LIM interaction domains. As protein–protein interacting molecules, PDZ and LIM domains function as scaffolds to bind to a variety of proteins. The PDLIMs are composed of evolutionarily conserved proteins found throughout different species. They can participate in cell signal transduction by mediating the interaction of signal molecules. They are involved in many important physiological processes, such as cell differentiation, proliferation, migration, and the maintenance of cellular structural integrity. Studies have shown that dysregulation of the PDLIMs leads to tumor formation and development. In this paper, we review and integrate the current knowledge on PDLIMs. The structure and function of the PDZ and LIM structural domains and the role of the PDLIMs in tumor development are described.

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McWilliams, Ryan R., Sophia Y. Breusegem, Kelley F. Brodsky, Eunjoon Kim, Moshe Levi, and R. Brian Doctor. "Shank2E binds NaPi cotransporter at the apical membrane of proximal tubule cells." American Journal of Physiology-Cell Physiology 289, no. 4 (October 2005): C1042—C1051. http://dx.doi.org/10.1152/ajpcell.00568.2004.

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Proteins expressing postsynaptic density (PSD)-95/ Drosophila disk large (Dlg)/zonula occludens-1 (ZO-1) (PDZ) domains are commonly involved in moderating receptor, channel, and transporter activities at the plasma membrane in a variety of cell types. At the apical membrane of renal proximal tubules (PT), the type IIa NaPi cotransporter (NaPi-IIa) binds specific PDZ domain proteins. Shank2E is a spliceoform of a family of PDZ proteins that is concentrated at the apical domain of liver and pancreatic epithelial cell types and is expressed in kidney. In the present study, immunoblotting of enriched plasma membrane fractions and immunohistology found Shank2E concentrated at the brush border membrane of rat PT cells. Confocal localization of Flag-Shank2E and enhanced green fluorescent protein-NaPi-IIa in cotransfected OK cells showed these proteins colocalized in the apical microvilli of this PT cell model. Shank2E coimmunoprecipitated with NaPi-IIa from rat renal cortex tissue and HA-NaPi-IIa coprecipitated with Flag-Shank2E in cotransfected human embryonic kidney HEK cells. Domain analysis showed that the PDZ domain of Shank2E specifically bound NaPi-IIa and truncation of the COOH-terminal TRL motif from NaPi-IIa abolished this binding, and Far Western blotting showed that the Shank2E- NaPi-IIa interaction occurred directly between the two proteins. NaPi-IIa activity is regulated by moderating its abundance in the apical membrane. High-Pi conditions induce NaPi-IIa internalization and degradation. In both rat kidney PT cells and OK cells, shifting to high-Pi conditions induced an acute internal redistribution of Shank2E and, in OK cells, a significant degree of degradation. In sum, Shank2E is concentrated in the apical domain of renal PT cells, specifically binds NaPi-IIa via PDZ interactions, and undergoes Pi-induced internalization.

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Jeleń, Filip, Arkadiusz Oleksy, Katarzyna Smietana, and Jacek Otlewski. "PDZ domains - common players in the cell signaling." Acta Biochimica Polonica 50, no. 4 (December 31, 2003): 985–1017. http://dx.doi.org/10.18388/abp.2003_3628.

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PDZ domains are ubiquitous protein interaction modules that play a key role in cellular signaling. Their binding specificity involves recognition of the carboxyl-terminus of various proteins, often belonging to receptor and ion channel families. PDZ domains also mediate more complicated molecular networks through PDZ-PDZ interactions, recognition of internal protein sequences or phosphatidylinositol moieties. The domains often form a tandem of multiple copies, but equally often such tandems or single PDZ domain occur in combination with other signaling domains (for example SH3, DH/PH, GUK, LIM, CaMK). Common occurrence of PDZ domains in Metazoans strongly suggests that their evolutionary appearance results from the complication of signaling mechanisms in multicellular organisms. Here, we focus on their structure, specificity and role in signaling pathways.

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KIMBER, Wendy A., Laura TRINKLE-MULCAHY, Peter C. F. CHEUNG, Maria DEAK, Louisa J. MARSDEN, Agnieszka KIELOCH, Stephen WATT, et al. "Evidence that the tandem-pleckstrin-homology-domain-containing protein TAPP1 interacts with Ptd(3,4)P2 and the multi-PDZ-domain-containing protein MUPP1 in vivo." Biochemical Journal 361, no. 3 (January 25, 2002): 525–36. http://dx.doi.org/10.1042/bj3610525.

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PtdIns(3,4,5)P3 is an established second messenger of growth-factor and insulin-induced signalling pathways. There is increasing evidence that one of the immediate breakdown products of PtdIns(3,4,5)P3, namely PtdIns(3,4)P2, whose levels are elevated by numerous extracellular agonists, might also function as a signalling molecule. Recently, we identified two related pleckstrin-homology (PH)-domain-containing proteins, termed ‘tandem-PH-domain-containing protein-1’ (TAPP1) and TAPP2, which interacted in vitro with high affinity with PtdIns(3,4)P2, but did not bind PtdIns(3,4,5)P3 or other phosphoinositides. In the present study we demonstrate that stimulation of Swiss 3T3 or 293 cells with agonists that stimulate PtdIns(3,4)P2 production results in the marked translocation of TAPP1 to the plasma membrane. This recruitment is dependent on a functional PtdIns(3,4)P2-binding PH domain and is inhibited by wortmannin, a phosphoinositide 3-kinase inhibitor that prevents PtdIns(3,4)P2 generation. A search for proteins that interact with TAPP1 identified the multi-PDZ-containing protein termed ‘MUPP1’, a protein possessing 13 PDZ domains and no other known modular or catalytic domains [PDZ is postsynaptic density protein (PSD-95)/Drosophila disc large tumour suppressor (dlg)/tight junction protein (ZO1)]. We demonstrate that immunoprecipitation of endogenously expressed TAPP1 from 293-cell lysates results in the co-immunoprecipitation of endogenous MUPP1, indicating that these proteins are likely to interact with each other physiologically. We show that TAPP1 and TAPP2 interact with the 10th and 13th PDZ domain of MUPP1 through their C-terminal amino acids. The results of the present study suggest that TAPP1 and TAPP2 could function in cells as adapter proteins to recruit MUPP1, or other proteins that they may interact with, to the plasma membrane in response to signals that elevate PtdIns(3,4)P2.

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Dudola, Dániel, Anett Hinsenkamp, and Zoltán Gáspári. "Ensemble-Based Analysis of the Dynamic Allostery in the PSD-95 PDZ3 Domain in Relation to the General Variability of PDZ Structures." International Journal of Molecular Sciences 21, no. 21 (November 6, 2020): 8348. http://dx.doi.org/10.3390/ijms21218348.

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PDZ domains are abundant interaction hubs found in a number of different proteins and they exhibit characteristic differences in their structure and ligand specificity. Their internal dynamics have been proposed to contribute to their biological activity via changes in conformational entropy upon ligand binding and allosteric modulation. Here we investigate dynamic structural ensembles of PDZ3 of the postsynaptic protein PSD-95, calculated based on previously published backbone and side-chain S2 order parameters. We show that there are distinct but interdependent structural rearrangements in PDZ3 upon ligand binding and the presence of the intramolecular allosteric modulator helix α3. We have also compared these rearrangements in PDZ1-2 of PSD-95 and the conformational diversity of an extended set of PDZ domains available in the PDB database. We conclude that although the opening-closing rearrangement, occurring upon ligand binding, is likely a general feature for all PDZ domains, the conformer redistribution upon ligand binding along this mode is domain-dependent. Our findings suggest that the structural and functional diversity of PDZ domains is accompanied by a diversity of internal motional modes and their interdependence.

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Giallourakis, C. "A molecular-properties-based approach to understanding PDZ domain proteins and PDZ ligands." Genome Research 16, no. 8 (June 29, 2006): 1056–72. http://dx.doi.org/10.1101/gr.5285206.

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Kachinsky, Amy M., Stanley C. Froehner, and Sharon L. Milgram. "A PDZ-containing Scaffold Related to the Dystrophin Complex at the Basolateral Membrane of Epithelial Cells." Journal of Cell Biology 145, no. 2 (April 19, 1999): 391–402. http://dx.doi.org/10.1083/jcb.145.2.391.

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Membrane scaffolding complexes are key features of many cell types, serving as specialized links between the extracellular matrix and the actin cytoskeleton. An important scaffold in skeletal muscle is the dystrophin-associated protein complex. One of the proteins bound directly to dystrophin is syntrophin, a modular protein comprised entirely of interaction motifs, including PDZ (protein domain named for PSD-95, discs large, ZO-1) and pleckstrin homology (PH) domains. In skeletal muscle, the syntrophin PDZ domain recruits sodium channels and signaling molecules, such as neuronal nitric oxide synthase, to the dystrophin complex. In epithelia, we identified a variation of the dystrophin complex, in which syntrophin, and the dystrophin homologues, utrophin and dystrobrevin, are restricted to the basolateral membrane. We used exogenously expressed green fluorescent protein (GFP)-tagged fusion proteins to determine which domains of syntrophin are responsible for its polarized localization. GFP-tagged full-length syntrophin targeted to the basolateral membrane, but individual domains remained in the cytoplasm. In contrast, the second PH domain tandemly linked to a highly conserved, COOH-terminal region was sufficient for basolateral membrane targeting and association with utrophin. The results suggest an interaction between syntrophin and utrophin that leaves the PDZ domain of syntrophin available to recruit additional proteins to the epithelial basolateral membrane. The assembly of multiprotein signaling complexes at sites of membrane specialization may be a widespread function of dystrophin-related protein complexes.

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Lee, Choongho, and Laimonis A. Laimins. "Role of the PDZ Domain-Binding Motif of the Oncoprotein E6 in the Pathogenesis of Human Papillomavirus Type 31." Journal of Virology 78, no. 22 (November 15, 2004): 12366–77. http://dx.doi.org/10.1128/jvi.78.22.12366-12377.2004.

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ABSTRACT A number of PDZ domain-containing proteins have been identified as binding partners for the oncoprotein E6 of the high-risk type human papillomaviruses (HPVs). These include hDlg, hScrib, MAGI-1, MAGI-2, MAGI-3, and MUPP1. The PDZ domain-binding motif (-X-T-X-V) at the carboxy terminus of E6 is essential for targeting PDZ proteins for proteasomal degradation. The presence of this motif only in the high-risk HPVs suggests its possible role in HPV-induced oncogenesis. To investigate the role of the PDZ domain-binding motif of E6 in the HPV life cycle, two mutant HPV31 genomes were constructed: E6ValΔ, with a deletion of the last amino acid residue of E6 (valine), and E6ETQVΔ, with a deletion of the entire PDZ domain-binding motif of E6 (ETQV). Three human foreskin keratinocyte (HFK) cell lines were established which maintained transfected wild-type HPV31 or either of two mutant genomes. Cells containing either of two mutant genomes were significantly retarded in their growth rates and reduced in their viral copy numbers compared to those transfected with wild-type genomes. Western analysis did not reveal any significant changes in the levels of PDZ proteins following stable transfection of any HPV31 genomes into HFKs. Although the E6ETQVΔ-transfected HFKs exhibited a pattern of morphological differentiation that appeared different from the HPV31 wild-type-transfected HFKs in organotypic raft cultures, immunohistochemical analysis failed to identify substantial changes in the differentiation-dependent membrane localization of hDlg proteins. These results suggest that binding of E6 to PDZ proteins modulates the early viral functions such as proliferation and maintenance of the viral copy number in undifferentiated cells.

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Alewine, Christine, Olav Olsen, James B. Wade, and Paul A. Welling. "TIP-1 Has PDZ Scaffold Antagonist Activity." Molecular Biology of the Cell 17, no. 10 (October 2006): 4200–4211. http://dx.doi.org/10.1091/mbc.e06-02-0129.

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PDZ proteins usually contain multiple protein–protein interaction domains and act as molecular scaffolds that are important for the generation and maintenance of cell polarity and cell signaling. Here, we identify and characterize TIP-1 as an atypical PDZ protein that is composed almost entirely of a single PDZ domain and functions as a negative regulator of PDZ-based scaffolding. We found that TIP-1 competes with the basolateral membrane mLin-7/CASK complex for interaction with the potassium channel Kir 2.3 in model renal epithelia. Consequently, polarized plasma membrane expression of Kir 2.3 is disrupted resulting in pronounced endosomal targeting of the channel, similar to the phenotype observed for mutant Kir 2.3 channels lacking the PDZ-binding motif. TIP-1 is ubiquitously expressed, raising the possibility that TIP-1 may play a similar role in regulating the expression of other membrane proteins containing a type I PDZ ligand.

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Gavarini, Sophie, Carine Bécamel, Christophe Altier, Philippe Lory, Joël Poncet, Jan Wijnholds, Joël Bockaert, and Philippe Marin. "Opposite Effects of PSD-95 and MPP3 PDZ Proteins on Serotonin 5-Hydroxytryptamine2C Receptor Desensitization and Membrane Stability." Molecular Biology of the Cell 17, no. 11 (November 2006): 4619–31. http://dx.doi.org/10.1091/mbc.e06-03-0218.

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PSD-95/Disc large/Zonula occludens 1 (PDZ) domain-containing proteins (PDZ proteins) play an important role in the targeting and the trafficking of transmembrane proteins. Our previous studies identified a set of PDZ proteins that interact with the C terminus of the serotonin 5-hydroxytryptamine (5-HT)2C receptor. Here, we show that the prototypic scaffolding protein postsynaptic density-95 (PSD-95) and another membrane-associated guanylate kinase, MAGUK p55 subfamily member 3 (MPP3), oppositely regulate desensitization of the receptor response in both heterologous cells and mice cortical neurons in primary culture. PSD-95 increased desensitization of the 5-HT2C receptor-mediated Ca2+ response, whereas MPP3 prevented desensitization of the Ca2+ response. The effects of the PDZ proteins on the desensitization of the Ca2+ response were correlated with a differential regulation of cell surface expression of the receptor. Additional experiments were performed to assess how PDZ proteins globally modulate desensitization of the 5-HT2C receptor response in neurons, by using a peptidyl mimetic of the 5-HT2C receptor C terminus fused to the human immunodeficiency virus type-1 Tat protein transduction domain, which disrupts interaction between the 5-HT2C receptor and PDZ proteins. Transduction of this peptide inhibitor into cultured cortical neurons increased the desensitization of the 5-HT2C receptor-mediated Ca2+ response. This indicates that, overall, interaction of 5-HT2C receptors with PDZ proteins inhibits receptor desensitization in cortical neurons.

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Lue, R. A., E. Brandin, E. P. Chan, and D. Branton. "Two independent domains of hDlg are sufficient for subcellular targeting: the PDZ1-2 conformational unit and an alternatively spliced domain." Journal of Cell Biology 135, no. 4 (November 15, 1996): 1125–37. http://dx.doi.org/10.1083/jcb.135.4.1125.

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hDlg, a human homologue of the Drosophila Dig tumor suppressor, contains two binding sites for protein 4.1, one within a domain containing three PSD-95/Dlg/ZO-1 (PDZ) repeats and another within the alternatively spliced I3 domain. Here, we further define the PDZ-protein 4.1 interaction in vitro and show the functional role of both 4.1 binding sites in situ. A single protease-resistant structure formed by the entirety of both PDZ repeats 1 and 2 (PDZ1-2) contains the protein 4.1-binding site. Both this PDZ1-2 site and the I3 domain associate with a 30-kD NH2-terminal domain of protein 4.1 that is conserved in ezrin/radixin/moesin (ERM) proteins. We show that both protein 4.1 and the ezrin ERM protein interact with the murine form of hDlg in a coprecipitating immune complex. In permeabilized cells and tissues, either the PDZ1-2 domain or the I3 domain alone are sufficient for proper subcellular targeting of exogenous hDlg. In situ, PDZ1-2-mediated targeting involves interactions with both 4.1/ERM proteins and proteins containing the COOH-terminal T/SXV motif. I3-mediated targeting depends exclusively on interactions with 4.1/ERM proteins. Our data elucidates the multivalent nature of membrane-associated guanylate kinase homologue (MAGUK) targeting, thus beginning to define those protein interactions that are critical in MAGUK function.

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Nguyen, Minh M., Marie L. Nguyen, Georgina Caruana, Alan Bernstein, Paul F. Lambert, and Anne E. Griep. "Requirement of PDZ-Containing Proteins for Cell Cycle Regulation and Differentiation in the Mouse Lens Epithelium." Molecular and Cellular Biology 23, no. 24 (December 15, 2003): 8970–81. http://dx.doi.org/10.1128/mcb.23.24.8970-8981.2003.

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ABSTRACT The roles of PDZ domain-containing proteins such as Dlg and Scrib have been well described for Drosophila; however, their requirement for mammalian development is poorly understood. Here we show that Dlg, Scrib, MAGI1, MAGI3, and MPDZ are expressed in the mouse ocular lens. We demonstrate that the increase in proliferation and defects in cellular adhesion and differentiation observed in epithelia of lenses that express E6, a viral oncoprotein that can bind to several PDZ proteins, including the human homologs of Dlg and Scrib, is dependent on E6's ability to bind these proteins via their PDZ domains. Analyses of lenses from mice carrying an insertional mutation in Dlg (dlggt ) show increased proliferation and proliferation in spatially inappropriate regions of the lens, a phenotype similar to that of lenses expressing E6. The results from this study indicate that multiple PDZ domain-containing proteins, including Dlg and Scrib, may be required for maintaining the normal pattern of growth and differentiation in the lens. Furthermore, the phenotypic similarities among the Drosophila dlg mutant, the lenses of dlggt mice, and the lenses of E6 transgenic mice suggest that Dlg may have a conserved function in regulating epithelial cell growth and differentiation across species.

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Cousido-Siah, Alexandra, Laura Carneiro, Camille Kostmann, Peter Ecsedi, Laszlo Nyitray, Gilles Trave, and Gergo Gogl. "A scalable strategy to solve structures of PDZ domains and their complexes." Acta Crystallographica Section D Structural Biology 78, no. 4 (March 11, 2022): 509–16. http://dx.doi.org/10.1107/s2059798322001784.

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The human PDZome represents one of the largest globular domain families in the human proteome, with 266 instances. These globular domains typically interact with C-terminal peptide motifs found in thousands of human proteins. Despite previous efforts, not all PDZ domains have experimentally solved structures and most of their complexes remain to be solved. Here, a simple and cost-effective strategy is proposed for the crystallization of PDZ domains and their complexes. A human annexin A2 fusion tag was used as a crystallization chaperone and the structures of nine PDZ domains were solved, including five domains that had not yet been solved. Finally, these novel experimental structures were compared with AlphaFold predictions and it is speculated how predictions and experimental methods could cooperate in order to investigate the structural landscapes of entire domain families and interactomes.

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Alpi, Emanuele, Elena Landi, Manuela Barilari, Michela Serresi, Piero Salvadori, Angela Bachi, and Luciana Dente. "Channel-interacting PDZ protein, ‘CIPP’, interacts with proteins involved in cytoskeletal dynamics." Biochemical Journal 419, no. 2 (March 27, 2009): 289–300. http://dx.doi.org/10.1042/bj20081387.

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Neuronal CIPP (channel-interacting PDZ protein) is a multivalent PDZ protein that interacts with specific channels and receptors highly expressed in the brain. It is composed of four PDZ domains that behave as a scaffold to clusterize functionally connected proteins. In the present study, we selected a set of potential CIPP interactors that are involved directly or indirectly in mechanisms of cytoskeletal remodelling and membrane protrusion formation. For some of these, we first proved the direct binding to specific CIPP PDZ domains considered as autonomous elements, and then confirmed the interaction with the whole protein. In particular, the small G-protein effector IRSp53 (insulin receptor tyrosine kinase substrate protein p53) specifically interacts with the second PDZ domain of CIPP and, when co-transfected in cultured mammalian cells with a tagged full-length CIPP, it induces a marked reorganization of CIPP cytoplasmic localization. Large punctate structures are generated as a consequence of CIPP binding to the IRSp53 C-terminus. Analysis of the puncta nature, using various endocytic markers, revealed that they are not related to cytoplasmic vesicles, but rather represent multi-protein assemblies, where CIPP can tether other potential interactors.

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Zhang, Mingjie, and Wenning Wang. "Organization of Signaling Complexes by PDZ-Domain Scaffold Proteins." Accounts of Chemical Research 36, no. 7 (July 2003): 530–38. http://dx.doi.org/10.1021/ar020210b.

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Gardiner, John, Robyn Overall, and Jan Marc. "PDZ Domain Proteins: ‘Dark Matter’ of the Plan Proteome?" Molecular Plant 4, no. 6 (November 2011): 933–37. http://dx.doi.org/10.1093/mp/ssr043.

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Udugamasooriya, Gomika, Dorina Saro, and Mark R. Spaller. "Bridged Peptide Macrocycles as Ligands for PDZ Domain Proteins." Organic Letters 7, no. 7 (March 2005): 1203–6. http://dx.doi.org/10.1021/ol0475966.

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Zheng, M., H. Cheng, I. Banerjee, and J. Chen. "ALP/Enigma PDZ-LIM Domain Proteins in the Heart." Journal of Molecular Cell Biology 2, no. 2 (December 30, 2009): 96–102. http://dx.doi.org/10.1093/jmcb/mjp038.

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Adams, Marvin E., Heather A. Mueller, and Stanley C. Froehner. "In vivo requirement of the α-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4." Journal of Cell Biology 155, no. 1 (September 24, 2001): 113–22. http://dx.doi.org/10.1083/jcb.200106158.

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α-Syntrophin is a scaffolding adapter protein expressed primarily on the sarcolemma of skeletal muscle. The COOH-terminal half of α-syntrophin binds to dystrophin and related proteins, leaving the PSD-95, discs-large, ZO-1 (PDZ) domain free to recruit other proteins to the dystrophin complex. We investigated the function of the PDZ domain of α-syntrophin in vivo by generating transgenic mouse lines expressing full-length α-syntrophin or a mutated α-syntrophin lacking the PDZ domain (ΔPDZ). The ΔPDZ α-syntrophin displaced endogenous α- and β1-syntrophin from the sarcolemma and resulted in sarcolemma containing little or no syntrophin PDZ domain. As a consequence, neuronal nitric oxide synthase (nNOS) and aquaporin-4 were absent from the sarcolemma. However, the sarcolemmal expression and distribution of muscle sodium channels, which bind the α-syntrophin PDZ domain in vitro, were not altered. Both transgenic mouse lines were bred with an α-syntrophin–null mouse which lacks sarcolemmal nNOS and aquaporin-4. The full-length α-syntrophin, not the ΔPDZ form, reestablished nNOS and aquaporin-4 at the sarcolemma of these mice. Genetic crosses with the mdx mouse showed that neither transgenic syntrophin could associate with the sarcolemma in the absence of dystrophin. Together, these data show that the sarcolemmal localization of nNOS and aquaporin-4 in vivo depends on the presence of a dystrophin-bound α-syntrophin PDZ domain.

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Faulkner, Georgine, Alberto Pallavicini, Elide Formentin, Anna Comelli, Chiara Ievolella, Silvia Trevisan, Gladis Bortoletto, et al. "ZASP: A New Z-band Alternatively Spliced PDZ-motif Protein." Journal of Cell Biology 146, no. 2 (July 26, 1999): 465–75. http://dx.doi.org/10.1083/jcb.146.2.465.

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PDZ motifs are modular protein–protein interaction domains, consisting of 80–120 amino acid residues, whose function appears to be the direction of intracellular proteins to multiprotein complexes. In skeletal muscle, there are a few known PDZ-domain proteins, which include neuronal nitric oxide synthase and syntrophin, both of which are components of the dystrophin complex, and actinin-associated LIM protein, which binds to the spectrin-like repeats of α-actinin-2. Here, we report the identification and characterization of a new skeletal muscle protein containing a PDZ domain that binds to the COOH-terminal region of α-actinin-2. This novel 31-kD protein is specifically expressed in heart and skeletal muscle. Using antibodies produced to a fragment of the protein, we can show its location in the sarcomere at the level of the Z-band by immunoelectron microscopy. At least two proteins, 32 kD and 78 kD, can be detected by Western blot analysis of both heart and skeletal muscle, suggesting the existence of alternative forms of the protein. In fact, several forms were found that appear to be the result of alternative splicing. The transcript coding for this Z-band alternatively spliced PDZ motif (ZASP) protein maps on chromosome 10q22.3–10q23.2, near the locus for infantile-onset spinocerebellar ataxia.

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Jing, Ming, Joanna Bohl, Nicole Brimer, Michael Kinter, and Scott B. Vande Pol. "Degradation of Tyrosine Phosphatase PTPN3 (PTPH1) by Association with Oncogenic HumanPapillomavirus E6 Proteins." Journal of Virology 81, no. 5 (December 13, 2006): 2231–39. http://dx.doi.org/10.1128/jvi.01979-06.

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ABSTRACT Oncoproteins from DNA tumor viruses associate with critical cellular proteins to regulate cell proliferation, survival, and differentiation.Human papillomavirus (HPV) E6 oncoproteins have been previously shown to associate with a cellular HECT domain ubiquitin ligase termed E6AP (UBE3A). Here we show that the E6-E6AP complex associates with and targets the degradation of the protein tyrosine phosphatase PTPN3 (PTPH1) in vitro and in living cells. PTPN3 is a membrane-associated tyrosine phosphatase with FERM, PDZ, and PTP domains previously implicated in regulating tyrosine phosphorylation of growth factor receptors and p97 VCP (valosin-containing protein, termed Cdc48 in Saccharomyces cerevisiae) and is mutated in a subset of colon cancers. Degradation of PTPN3 by E6 requires E6AP, the proteasome, and an interaction between the carboxy terminus of E6 and the PDZ domain of PTPN3. In transduced keratinocytes, E6 confers reduced growth factor requirements, a function that requires the PDZ ligand of E6 and that can in part be replicated by inhibiting the expression of PTPN3. This report demonstrates the potential of E6 to regulate phosphotyrosine metabolism through the targeted degradation of a tyrosine phosphatase.

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Journal articles on the topic 'PDZ domain proteins'

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