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PDZ Domain (pdz + domain)
Selected AbstractsSulindac Inhibits Canonical Wnt Signaling by Blocking the PDZ Domain of the Protein Dishevelled,ANGEWANDTE CHEMIE, Issue 35 2009Ho-Jin Lee Dr. Neuer Nutzen: Der nichtsteroidale Entzündungshemmer Sulindac wechselwirkt direkt und spezifisch mit der PDZ-Domäne des Proteins Dishevelled (Dvl), einer zentralen intrazellulären Komponente des Wnt-Signalwegs. Sulindac bindet an die konventionelle Peptidbindetasche der Domäne (siehe Bild) und könnte durch ihr Blockieren das kanonische Wnt-Signal inhibieren und so einen chemischen Schutz vor Krebs bieten. [source] Identification and characterization of Xenopus OMP25DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2004Masafumi Inui This study describes the isolation of mitochondrial outer membrane protein 25 (OMP25) from Xenopus laevis and an analysis of its role in early development. X. laevis OMP25 (xOMP25) is a transmembrane protein of the mitochondrial outer membrane with a PDZ domain in the cytoplasmic tail, and an approximate molecular size of 25 kDa. We isolated xOMP25 from a cDNA library of X. laevis tailbud embryos. Amino acid sequence analysis of xOMP25 showed 57% identity to mouse OMP25, with 73% identity in the PDZ domains. XOMP25 mRNA is expressed maternally, and at a constant level throughout early development. The transcript is localized to eye, otic vesicle, branchial arch and neural tube. Mitochondrial targeting of an EGFP-fusion protein of xOMP25 was visualized using a mitochondria-specific fluorescent dye. Overexpression of xOMP25 in embryos caused curved axes, small eyes and disorganized head structures. Knockdown of xOMP25 protein using antisense morpholino oligonucleotides resulted in slightly shortened axes and decreased neural tissue. Although the mechanism remains unclear, our results implicate xOMP25 protein in the formation of the intact neural tube. [source] Redox-regulated affinity of the third PDZ domain in the phosphotyrosine phosphatase PTP-BL for cysteine-containing target peptidesFEBS JOURNAL, Issue 13 2005Lieke C. J. Van Den Berk PDZ domains are protein,protein interaction modules that are crucial for the assembly of structural and signalling complexes. They specifically bind to short C-terminal peptides and occasionally to internal sequences that structurally resemble such peptide termini. The binding of PDZ domains is dominated by the residues at the P0 and P,2 position within these C-terminal targets, but other residues are also important in determining specificity. In this study, we analysed the binding specificity of the third PDZ domain of protein tyrosine phosphatase BAS-like (PTP-BL) using a C-terminal combinatorial peptide phage library. Binding of PDZ3 to C-termini is preferentially governed by two cysteine residues at the P,1 and P,4 position and a valine residue at the P0 position. Interestingly, we found that this binding is lost upon addition of the reducing agent dithiothrietol, indicating that the interaction is disulfide-bridge-dependent. Site-directed mutagenesis of the single cysteine residue in PDZ3 revealed that this bridge formation does not occur intermolecularly, between peptide and PDZ3 domain, but rather is intramolecular. These data point to a preference of PTP-BL PDZ3 for cyclic C-terminal targets, which may suggest a redox state-sensing role at the cell cortex. [source] Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease,HUMAN MUTATION, Issue 6 2008Veerle Bogaerts Abstract In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5, and 3, regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration. Hum Mutat 29(6), 832,840, 2008. © 2008 Wiley-Liss, Inc. [source] PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2007C. Gragnoli Multiple genome-wide scans in different populations have linked the chromosome 12q24 region, known as NIDDM2 (non-insulin-dependent-diabetes, locus 2), to type 2 diabetes. Within NIDDM2 we examined the PSMD9 (proteasome modulator 9/Bridge-1) gene that encodes a PDZ-domain transcriptional coactivator of insulin production. Our goal was to identify a potential contribution of the PSMD9 gene to type 2 diabetes in Italians. We directly sequenced the entire gene PSMD9 in Italian type 2 diabetes patients (n,=,237) and controls subjects (n,=,215) and performed an association study with the identified gene variants. We found five single nucleotide polymorphisms (SNPs), A17V, IVS1+nt29, IVS3+nt460, IVS3+nt437, and E197G, which are not associated with disease in our case,control study. Furthermore, we identified two PSMD9 gene variants in type 2 diabetes patients, which produced nonconservative amino acid substitutions S143G and N166S within the PDZ domain and two other gene variants. Three out of four of these variants are absent from the control subjects screened. We propose that the three PSMD9 gene variants (S143G, N166S and G,>,A at IVS3+nt102), absent in control subjects, contribute rarely to late-onset type 2 diabetes in Italians. In fact, the frequency rate of such variants in unrelated cases equals 0.016. We may not exclude that PSMD9 gene variants may contribute, either commonly or rarely, to an increased risk of type 2 diabetes in other populations. J. Cell. Physiol. 212:568,571, 2007. © 2007 Wiley-Liss, Inc. [source] Identifying and reducing error in cluster-expansion approximations of protein energiesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 16 2010Seungsoo Hahn Abstract Protein design involves searching a vast space for sequences that are compatible with a defined structure. This can pose significant computational challenges. Cluster expansion is a technique that can accelerate the evaluation of protein energies by generating a simple functional relationship between sequence and energy. The method consists of several steps. First, for a given protein structure, a training set of sequences with known energies is generated. Next, this training set is used to expand energy as a function of clusters consisting of single residues, residue pairs, and higher order terms, if required. The accuracy of the sequence-based expansion is monitored and improved using cross-validation testing and iterative inclusion of additional clusters. As a trade-off for evaluation speed, the cluster-expansion approximation causes prediction errors, which can be reduced by including more training sequences, including higher order terms in the expansion, and/or reducing the sequence space described by thecluster expansion. This article analyzes the sources of error and introduces a method whereby accuracy can be improved by judiciously reducing the described sequence space. The method is applied to describe the sequence,stability relationship for several protein structures: coiled-coil dimers and trimers, a PDZ domain, and T4 lysozyme as examples with computationally derived energies, and SH3 domains in amphiphysin-1 and endophilin-1 as examples where the expanded pseudo-energies are obtained from experiments. Our open-source software package Cluster Expansion Version 1.0 allows users to expand their own energy function of interest and thereby apply cluster expansion to custom problems in protein design. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010 [source] Unusual binding interactions in PDZ domain crystal structures help explain binding mechanismsPROTEIN SCIENCE, Issue 4 2010Jonathan M. Elkins Abstract PDZ domains most commonly bind the C-terminus of their protein targets. Typically the C-terminal four residues of the protein target are considered as the binding motif, particularly the C-terminal residue (P0) and third-last residue (P-2) that form the major contacts with the PDZ domain's "binding groove". We solved crystal structures of seven human PDZ domains, including five of the seven PDLIM family members. The structures of GRASP, PDLIM2, PDLIM5, and PDLIM7 show a binding mode with only the C-terminal P0 residue bound in the binding groove. Importantly, in some cases, the P-2 residue formed interactions outside of the binding groove, providing insight into the influence of residues remote from the binding groove on selectivity. In the GRASP structure, we observed both canonical and noncanonical binding in the two molecules present in the asymmetric unit making a direct comparison of these binding modes possible. In addition, structures of the PDZ domains from PDLIM1 and PDLIM4 also presented here allow comparison with canonical binding for the PDLIM PDZ domain family. Although influenced by crystal packing arrangements, the structures nevertheless show that changes in the positions of PDZ domain side-chains and the ,B helix allow noncanonical binding interactions. These interactions may be indicative of intermediate states between unbound and fully bound PDZ domain and target protein. The noncanonical "perpendicular" binding observed potentially represents the general form of a kinetic intermediate. Comparison with canonical binding suggests that the rearrangement during binding involves both the PDZ domain and its ligand. [source] Solution structure of GOPC PDZ domain and its interaction with the C-terminal motif of neuroliginPROTEIN SCIENCE, Issue 9 2006Xiang Li Abstract GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) represents a PDZ domain-containing protein associated with the Golgi apparatus, which plays important roles in vesicular trafficking in secretory and endocytic pathways. GOPC interacts with many other proteins, such as the Wnt receptors Frizzled 8 and neuroligin via its PDZ domain. Neuroligin is a neural cell-adhesion molecule of the post-synapse, which binds to the presynapse molecule neurexin to form a heterotypic intercellular junction. Here we report the solution structure of the GOPC PDZ domain by NMR. Our results show that it is a canonical class I PDZ domain, which contains two ,-helices and six ,-strands. Using chemical shift perturbation experiments, we further studied the binding properties of the GOPC PDZ domain with the C-terminal motif of neuroligin. The observations showed that the ensemble of the interaction belongs to fast exchange with low affinity. The 3D model of the GOPC PDZ domain/neuroligin C-terminal peptide complex was constructed with the aid of the molecular dynamics simulation method. Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C-terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain-containing proteins. [source] Crystallization and preliminary X-ray crystallographic studies of the sixth PDZ domain of glutamate-receptor interacting protein 1 (GRIP1) from Rattus norvegicusACTA CRYSTALLOGRAPHICA SECTION D, Issue 6-2 2002Seong Ho Park The sixth PDZ domain from GRIP1 and its complex with the octapeptide of the liprin-,1 C-terminus were crystallized at 294,K by the hanging-drop vapour-diffusion method. The native crystal belongs to space group P6122 (or P6522), with unit-cell parameters a = b = 40.3, c = 222.9,Å. The complex crystal belongs to space group R32, with unit-cell parameters a = b = 117.8, c = 102.0,Å. Native and peptide-complex diffraction data were collected to resolutions of 1.5 and 1.8,Å, respectively, using synchrotron X-rays. [source] Structure of the first PDZ domain of human PSD-93ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 12 2009Monica Fiorentini The crystal structure of the PDZ1 domain of human PSD-93 has been determined to 2.0,Å resolution. The PDZ1 domain forms a crystallographic trimer that is also predicted to be stable in solution. The main contributions to the stabilization of the trimer seem to arise from interactions involving the PDZ1,PDZ2 linker region at the extreme C-terminus of PDZ1, implying that the oligomerization that is observed is not of biological significance in full-length PSD-93. Comparison of the structures of the binding cleft of PSD-93 PDZ1 with the previously reported structures of PSD-93 PDZ2 and PDZ3 as well as of the closely related human PSD-95 PDZ1 shows that they are very similar in terms of amino-acid composition. However, the cleft is significantly narrower in PSD-95. This could be part of the basis of peptide selectivity between PSD-93 PDZ1 and PSD-95 PDZ1. [source] Structure of the second PDZ domain from human zonula occludens 2ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2009Hui Chen Human zonula occludens 2 (ZO-2) protein is a multi-domain protein that consists of an SH3 domain, a GK domain and three copies of a PDZ domain with slight divergence. The three PDZ domains act as protein-recognition modules that may mediate protein assembly and subunit localization. The crystal structure of the second PDZ domain of ZO-2 (ZO-2 PDZ2) was determined by molecular replacement at 1.75,Å resolution, revealing a dimer in the asymmetric unit. The dimer is stabilized by extensive symmetrical domain-swapping of the ,1 and ,2 strands. Structural comparison shows that the ZO-2 PDZ2 homodimer may have a similar ligand-binding pattern to the ZO-1 PDZ2,connexin 43 complex. [source] Unusual binding interactions in PDZ domain crystal structures help explain binding mechanismsPROTEIN SCIENCE, Issue 4 2010Jonathan M. Elkins Abstract PDZ domains most commonly bind the C-terminus of their protein targets. Typically the C-terminal four residues of the protein target are considered as the binding motif, particularly the C-terminal residue (P0) and third-last residue (P-2) that form the major contacts with the PDZ domain's "binding groove". We solved crystal structures of seven human PDZ domains, including five of the seven PDLIM family members. The structures of GRASP, PDLIM2, PDLIM5, and PDLIM7 show a binding mode with only the C-terminal P0 residue bound in the binding groove. Importantly, in some cases, the P-2 residue formed interactions outside of the binding groove, providing insight into the influence of residues remote from the binding groove on selectivity. In the GRASP structure, we observed both canonical and noncanonical binding in the two molecules present in the asymmetric unit making a direct comparison of these binding modes possible. In addition, structures of the PDZ domains from PDLIM1 and PDLIM4 also presented here allow comparison with canonical binding for the PDLIM PDZ domain family. Although influenced by crystal packing arrangements, the structures nevertheless show that changes in the positions of PDZ domain side-chains and the ,B helix allow noncanonical binding interactions. These interactions may be indicative of intermediate states between unbound and fully bound PDZ domain and target protein. The noncanonical "perpendicular" binding observed potentially represents the general form of a kinetic intermediate. Comparison with canonical binding suggests that the rearrangement during binding involves both the PDZ domain and its ligand. [source] Identification and characterization of Xenopus OMP25DEVELOPMENT GROWTH & DIFFERENTIATION, Issue 5 2004Masafumi Inui This study describes the isolation of mitochondrial outer membrane protein 25 (OMP25) from Xenopus laevis and an analysis of its role in early development. X. laevis OMP25 (xOMP25) is a transmembrane protein of the mitochondrial outer membrane with a PDZ domain in the cytoplasmic tail, and an approximate molecular size of 25 kDa. We isolated xOMP25 from a cDNA library of X. laevis tailbud embryos. Amino acid sequence analysis of xOMP25 showed 57% identity to mouse OMP25, with 73% identity in the PDZ domains. XOMP25 mRNA is expressed maternally, and at a constant level throughout early development. The transcript is localized to eye, otic vesicle, branchial arch and neural tube. Mitochondrial targeting of an EGFP-fusion protein of xOMP25 was visualized using a mitochondria-specific fluorescent dye. Overexpression of xOMP25 in embryos caused curved axes, small eyes and disorganized head structures. Knockdown of xOMP25 protein using antisense morpholino oligonucleotides resulted in slightly shortened axes and decreased neural tissue. Although the mechanism remains unclear, our results implicate xOMP25 protein in the formation of the intact neural tube. [source] Expression of zonula occludens-1 (ZO-1) and the transcription factor ZO-1-associated nucleic acid-binding protein (ZONAB),MsY3 in glial cells and colocalization at oligodendrocyte and astrocyte gap junctions in mouse brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2005Mihai C. Penes Abstract The PDZ domain-containing protein zonula occludens-1 (ZO-1) interacts with several members of the connexin (Cx) family of gap junction-forming proteins and has been localized to gap junctions, including those containing Cx47 in oligodendrocytes. We now provide evidence for ZO-1 expression in astrocytes in vivo and association with astrocytic connexins by confocal immunofluorescence demonstration of ZO-1 colocalization with astrocytic Cx30 and Cx43, and by ZO-1 coimmunoprecipitation with Cx30 and Cx43. Evidence for direct interaction of Cx30 with ZO-1 was obtained by pull-down assays that indicated binding of Cx30 to the second of the three PDZ domains in ZO-1. Further, we investigated mouse Y-box transcription factor MsY3, the canine ortholog of which has been termed ZO-1-associated nucleic acid-binding protein (ZONAB) and previously reported to interact with ZO-1. By immunofluorescence using specific antimouse ZONAB antibody, ZONAB was found to be associated with oligodendrocytes throughout mouse brain and spinal cord, and to be colocalized with oligodendrocytic Cx47 and Cx32 as well as with astrocytic Cx43. Our results extend the CNS cell types that express the multifunctional protein ZO-1, demonstrate an additional connexin (Cx30) that directly interacts with ZO-1, and show for the first time the association of a transcription factor (ZONAB) with ZO-1 localized to oligodendrocyte and astrocyte gap junctions. Given previous observations that ZONAB and ZO-1 in combination regulate gene expression, our results suggest roles of glial gap junction-mediated anchoring of signalling molecules in a wide variety of glial homeostatic processes. [source] Redox-regulated affinity of the third PDZ domain in the phosphotyrosine phosphatase PTP-BL for cysteine-containing target peptidesFEBS JOURNAL, Issue 13 2005Lieke C. J. Van Den Berk PDZ domains are protein,protein interaction modules that are crucial for the assembly of structural and signalling complexes. They specifically bind to short C-terminal peptides and occasionally to internal sequences that structurally resemble such peptide termini. The binding of PDZ domains is dominated by the residues at the P0 and P,2 position within these C-terminal targets, but other residues are also important in determining specificity. In this study, we analysed the binding specificity of the third PDZ domain of protein tyrosine phosphatase BAS-like (PTP-BL) using a C-terminal combinatorial peptide phage library. Binding of PDZ3 to C-termini is preferentially governed by two cysteine residues at the P,1 and P,4 position and a valine residue at the P0 position. Interestingly, we found that this binding is lost upon addition of the reducing agent dithiothrietol, indicating that the interaction is disulfide-bridge-dependent. Site-directed mutagenesis of the single cysteine residue in PDZ3 revealed that this bridge formation does not occur intermolecularly, between peptide and PDZ3 domain, but rather is intramolecular. These data point to a preference of PTP-BL PDZ3 for cyclic C-terminal targets, which may suggest a redox state-sensing role at the cell cortex. [source] Helicobacter pylori CagA: Analysis of Sequence Diversity in Relation to Phosphorylation Motifs and Implications for the Role of CagA as a Virulence FactorHELICOBACTER, Issue 3 2001Doyle J. Evans Jr Abstract CagA is transported into host target cells and subsequently phosphorylated. Clearly this is a mechanism by which Helicobacter pylori could take control of one or more host cell signal transduction pathways. Presumably the end result of this interaction favors survival of H. pylori, irrespective of eventual damage to the host cell. CagA is noted for its amino acid (AA) sequence diversity, both within and outside the variable region of the molecule. The primary purpose of this review is to examine how variation in the type and number of CagA phosphorylation sites might determine the outcome of infection by different strains of H. pylori. The answer to this question could help to explain the widely disparate results obtained when H. pylori CagA status has been compared to type and severity of disease outcome in different populations, that is in different countries. Analysis of all available CagA sequences revealed that CagA contains both tyrosine phosphorylation motifs (TPMs) and cyclic-AMP-dependent phosphorylation motifs (CPMs). There are two potential CPMs near the N-terminus of CagA and at least two in the repeat region; these are not all equally well conserved. We also defined a 48-residue AA sequence, which includes the N-terminal TPM at tyrosine (Y)-122, which distinguishes between Eastern (Hong Kong-Taiwan-Japan-Thailand) H. pylori isolates and those from the West (Europe-Africa-the Americas-Australia). All 28 of the Eastern type CagA proteins have a functional N-terminal TPM whereas 11 of 47 (23.4%) of the Western type contain an inactive motif, with threonine (T) replacing the critical aspartic acid (D) residue. Only 13 of 24 (54%) known CagA sequences have an active TPM in the repeat region and only one has two TPMs in this region. The potential TPM near the C-terminus of CagA is not likely to be important since only 3 of 24 (12.5%) sequences were found to be intact. Protein database searches revealed that the AA sequence immediately following the TPM at Y-122 in CagA is homologous with a pair of PDZ domains which are common in signal transducing proteins, particularly tyrosine phosphatases. This provides a theoretical link between CagA and many of the observed responses of host cells to H. pylori. In summary, not all CagA proteins are equal in their potential for initiating host cell responses via signal transduction pathways. The degree of functional diversity of this protein depends upon which phosphorylation motifs are critical to the biological activity of CagA. [source] Unusual binding interactions in PDZ domain crystal structures help explain binding mechanismsPROTEIN SCIENCE, Issue 4 2010Jonathan M. Elkins Abstract PDZ domains most commonly bind the C-terminus of their protein targets. Typically the C-terminal four residues of the protein target are considered as the binding motif, particularly the C-terminal residue (P0) and third-last residue (P-2) that form the major contacts with the PDZ domain's "binding groove". We solved crystal structures of seven human PDZ domains, including five of the seven PDLIM family members. The structures of GRASP, PDLIM2, PDLIM5, and PDLIM7 show a binding mode with only the C-terminal P0 residue bound in the binding groove. Importantly, in some cases, the P-2 residue formed interactions outside of the binding groove, providing insight into the influence of residues remote from the binding groove on selectivity. In the GRASP structure, we observed both canonical and noncanonical binding in the two molecules present in the asymmetric unit making a direct comparison of these binding modes possible. In addition, structures of the PDZ domains from PDLIM1 and PDLIM4 also presented here allow comparison with canonical binding for the PDLIM PDZ domain family. Although influenced by crystal packing arrangements, the structures nevertheless show that changes in the positions of PDZ domain side-chains and the ,B helix allow noncanonical binding interactions. These interactions may be indicative of intermediate states between unbound and fully bound PDZ domain and target protein. The noncanonical "perpendicular" binding observed potentially represents the general form of a kinetic intermediate. Comparison with canonical binding suggests that the rearrangement during binding involves both the PDZ domain and its ligand. [source] Crystallographic characterization of the PDZ1 domain of the human Na+/H+ exchanger regulatory factorACTA CRYSTALLOGRAPHICA SECTION D, Issue 5 2001Gordon Webster The Na+/H+ exchanger regulatory factor (NHERF) contains two PDZ domains that mediate the assembly of transmembrane and cytosolic proteins into functional signal transduction complexes. The human NHERF PDZ1 domain, which spans residues 11,99, interacts specifically with carboxy-terminal residues of the ,2 adrenergic receptor and the cystic fibrosis transmembrane conductance regulator. The NHERF PDZ1 was expressed in Escherichia coli as a soluble protein, purified and crystallized in the unbound form using the vapor-diffusion method with 2,M ammonium sulfate as the precipitant. Diffraction data were collected to 1.5,Å resolution using synchrotron radiation. The crystals belong to space group P3121 or P3221, with unit-cell parameters a = b = 51.6, c = 58.9,Å, and one molecule in the asymmetric unit. [source] Crystallization and preliminary X-ray diffraction studies of the guanylate kinase-like domain of PSD-95 protein from ratACTA CRYSTALLOGRAPHICA SECTION D, Issue 4 2001Jung Jin Kim The PSD-95 (postsynaptic density-95) protein, one of the members of the MAGUK (membrane-associated guanylate kinase) family, is composed of three PDZ domains, one SH3 domain and one guanylate kinase-like (GK) domain. The GK domain mediates the scaffolding function of PSD-95 by protein,protein interaction. Here, the GK domain was subcloned, expressed as an intein fusion protein, purified without the intein and then crystallized at room temperature by the hanging-drop vapour-diffusion method using PEG 8000 as a precipitant. The complete native data set was collected to a resolution of 2.35,Å using flash-cooling. The crystals belong to the primitive tetragonal space group P43 (or P41), with unit-cell parameters a = b = 70.03,(4), c = 37.64,(1),Å. [source] Structure of the second PDZ domain from human zonula occludens 2ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2009Hui Chen Human zonula occludens 2 (ZO-2) protein is a multi-domain protein that consists of an SH3 domain, a GK domain and three copies of a PDZ domain with slight divergence. The three PDZ domains act as protein-recognition modules that may mediate protein assembly and subunit localization. The crystal structure of the second PDZ domain of ZO-2 (ZO-2 PDZ2) was determined by molecular replacement at 1.75,Å resolution, revealing a dimer in the asymmetric unit. The dimer is stabilized by extensive symmetrical domain-swapping of the ,1 and ,2 strands. Structural comparison shows that the ZO-2 PDZ2 homodimer may have a similar ligand-binding pattern to the ZO-1 PDZ2,connexin 43 complex. [source] Disrupting specific PDZ domain-mediated interactions for therapeutic benefitBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2009Miles D Houslay The past two decades have seen an immense increase in our appreciation of the vast range of signalling processes and supporting machinery that occur in cells. Pivotal to this is the notion of signal compartmentalization (compartmentation). Targeting by protein domains is critical in allowing signalling complexes to be assembled at defined intracellular locales so as to confer correct function. This issue of the BJP contains two intriguing articles that address functional protein,protein interactions involving PDZ domains [Post-synaptic density protein-95 (PSD95), Drosophila disc large tumour suppressor (DlgA) and Zonula occludens-1 protein (zo-1)] and their implications for signalling. One involves targeting of neuronal nitric oxide synthase to the N-methyl D-aspartic acid (NMDA) receptor via the PDZ-containing signal scaffold, PSD95. The other involves controlling multiple receptor inputs into regulation of epithelial Na+K+ -ATPase through the PDZ-containing signal scaffold Pals-associated tight junction. Highlighted is not only the use of dominant-negative strategies to identify the importance of targeting at specific types of PDZ domains but also the exciting notion that small molecule disruptors of interaction at specific PDZ domains can be generated for potential therapeutic application. [source] Structural Diversity of PDZ,Lipid InteractionsCHEMBIOCHEM, Issue 4 2010Rodrigo Gallardo Abstract PDZ domains are globular protein modules that are over-and-above appreciated for their interaction with short peptide motifs found in the cytosolic tail of membrane receptors, channels, and adhesion molecules. These domains predominate in scaffold molecules that control the assembly and the location of large signaling complexes. Studies have now emerged showing that PDZ domains can also interact with membrane lipids, and in particular with phosphoinositides. Phosphoinositides control various aspects of cell signaling, vesicular trafficking, and cytoskeleton remodeling. When investigated, lipid binding appears to be extremely relevant for PDZ protein functionality. Studies point to more than one mechanism for PDZ domains to associate with lipids. Few studies have been focused on the structural basis of PDZ,phosphoinositide interactions, and the biological consequences of such interactions. Using the current knowledge on syntenin-1, syntenin-2, PTP-Bas, PAR-3 and PICK1, we recapitulate our understanding of the structural and biochemical aspects of PDZ,lipid interactions and the consequences for peptide interactions. [source] | ||||||||||||||||