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At least 955 records · Page 53Linked to original sources
PubMed2002

Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis.

Threshold levels of individual NFAT factors appear to be critical for apoptosis induction in effector T cells. In these cells, the short isoform A of NFATc1 is induced to high levels due to the autoregulation of the NFATc1 promoter P1 by NFATs. P1 is located within a CpG island in front of exon 1, represents a DNase I hypersensitive chromatin site, and harbors several sites for binding of inducible transcription factors, including a tandemly arranged NFAT site. A second promoter, P2, before exon 2, is not controlled by NFATs and directs synthesis of the longer NFATc1/B+C isoforms. Contrary to other NFATs, NFATc1/A is unable to promote apoptosis, suggesting that NFATc1/A enhances effector functions without promoting apoptosis of effector T cells.

Alternative Splicing↗
PubMed2003

Production of ribosome components in effector CD4+ T cells is accelerated by TCR stimulation and coordinated by ERK-MAPK.

Effector CD4+ T cells rapidly activate high-level cytokine expression following TCR stimulation. Consistent with accelerated protein production in these cells, global mRNA profiles revealed that, after cytokines, the most impressive cluster of activated genes encode rRNA-maturation factors. Activation of these genes was ERK-MAPK dependent, accompanied by increased rRNA transcription and faster maturation kinetics, and much greater in effector CD4+ T cells than in naive cells. Ribosomal protein subunit (RPS) synthesis was also ERK-MAPK dependent and increased to match rRNA production, but without evident increase in RPS mRNA. Instead, stimulation promoted polysome loading of RPS mRNA via cis-acting, 5'-terminal oligopyrimidines. These results demonstrate how, in response to extracellular signals, effector CD4+ T cells coordinately increase multiple ribosomal components to accommodate burgeoning cytokine production.

Animals↗
PubMed2000

Modulation of host signaling by a bacterial mimic: structure of the Salmonella effector SptP bound to Rac1.

Salmonella spp. utilize a specialized protein secretion system to deliver a battery of effector proteins into host cells. Several of these effectors stimulate Cdc42- and Rac1-dependent cytoskeletal changes that promote bacterial internalization. These potentially cytotoxic alterations are rapidly reversed by the effector SptP, a tyrosine phosphatase and GTPase activating protein (GAP) that targets Cdc42 and Rac1. The 2.3 A resolution crystal structure of an SptP-Rac1 transition state complex reveals an unusual GAP architecture that mimics host functional homologs. The phosphatase domain possesses a conserved active site but distinct surface properties. Binding to Rac1 induces a dramatic stabilization in SptP of a four-helix bundle that makes extensive contacts with the Switch I and Switch II regions of the GTPase.

Aluminum Compounds↗
PubMed2003

Regulation of the generation and maintenance of T-cell memory: a direct, default pathway from effectors to memory cells.

Memory T cells are derived directly from effector cells without need for additional antigen, TcR triggering or induced cytokines. A large fraction of effectors can become memory cells without division, supporting a default pathway with little further differentiation. This suggests that the same signals during infection/vaccination determine the extent and nature of both effector and memory cell development.

Animals↗
PubMed2000

Effector proteins of phytopathogenic bacteria: bifunctional signals in virulence and host recognition.

Phytopathogenic bacteria deliver effectors of disease into plant hosts via a Type III secretion system. These Type III effectors have genetically determined roles in virulence. They also are among the components recognized by the putative receptors of the plant innate immune system. Recent breakthroughs include localization of some of these Type III effectors to specific host cell compartments, and the first dissection of pathogenicity islands that carry them.

Bacteria↗
PubMed2000

Prevalence and polymorphism of genes encoding translocated effector proteins among clinical isolates of Salmonella enterica.

Pathogenic Salmonella enterica strains are capable of causing local and/or systemic infections. They employ two type III secretion systems to translocate an array of virulence-associated proteins (effector proteins) directly into the cytosol of target cells of the host. Earlier data had shown that changes in the repertoire of translocated effector proteins may contribute to the adaptation of Salmonella strains to new hosts and to the emergence of epidemic strains. Using PCR and Southern blot techniques the presence of and the polymorphism among the genes encoding the translocated effector proteins SopB, SopD, SopE, SopE2, SipA, SipB, SipC, AvrA, and SptP was studied in 71 phylogenetically well characterised S. enterica subspecies I (subspecies enterica) strains of the SARB collection and in 209 clinical and epidemic isolates of S. enterica subspecies I belonging to various serovars, phage types, and genotypes. All these Salmonella strains harbour all these respective genes with the exception of sopE and avrA which have been identified in only some of them. Several of the studied genes display genetic polymorphisms (RFLP). These RFLP patterns did not show a strict correlation with the genetic distance, the grouping genes in order to understand their role in the evolution of Salmonella as a pathogen.

Actins↗
PubMed1991

Schistosoma mansoni: larval damage and role of effector cell(s) in the synergy between vaccine immunity and praziquantel treatment.

A number of authors have demonstrated that the schistosomicidal compound, Praziquantel (Pzq), depends for its action upon the immune status of the host (Sabah et al. 1985; Brindley & Sher, 1987; Doenhoff et al. 1987). We have attempted to define the synergistic interaction between immuno- and chemotherapy further, using the murine irradiated vaccine model of schistosomiasis mansoni. In vaccinated mice, resistance operates in the skin but not the lungs; drug targeted towards lung-stage worms exacerbates lung-phase immunity, however, as depicted by the increased number and size of inflammatory reactions in the pulmonary tissues. Parasites are often found trapped within such foci. In the present investigation, light and ultrastructural studies have been utilized to examine the nature and extent of damage inflicted upon lung-stage larvae recovered from day 6 Pzq-treated vaccinated mice. Such studies have revealed that damage involves muscle disorganization, internal disruption and occasionally, loss of the tegument; in the latter case, cells are often seen attached to the denuded lung worms. To identify the crucial cellular effector cell(s) involved in the synergy between immuno- and chemotherapy, cell depletion studies have been performed in vivo. It would appear from these experiments that eosinophils or lymphocytes rather than neutrophils or macrophages are important effector cells in this synergy. Histological studies argue in favour of eosinophils being the key effector cells.

Animals↗
PubMedDate not supplied

Preparation and characterization of a DOTA-lysine-biotin conjugate as an effector molecule for pretargeted radionuclide therapy.

Pretargeted radionuclide therapy depends on the establishment of a high concentration of secondary binding sites at a tumor to which low-molecular weight radiolabeled effector molecules can be directed. This study describes the simple synthesis of an effector molecule and its subsequent characterization to determine the extent to which it complied with the ideal requirements of such a compound. (Epsilon)-DOTA-(alpha)-biotinamidolysine (DLB) was synthesized in high yield and purity using conventional SPPS methodology. High radiochemical purities were obtained when labeled with several potentially useful radionuclides. The radiolabeled analogue bound to streptavidin efficiently with a stoichiometry similar to that of native biotin and showed high stability in serum and upon challenge with acid conditions. Biodistribution studies in normal animals showed a rapid rate of clearance from the blood and low retention of radioactivity by normal tissues. This design of effector molecule therefore shows promise for further pretargeted radionuclide therapy studies.

Animals↗
PubMed2001

Protein kinase C effectors bind to multidrug ABC transporters and inhibit their activity.

P-Glycoprotein and homologous multidrug transporters contain a phosphorylatable linker sequence that was proposed to control drug efflux on the basis that it was indeed phosphorylated in vitro and in vivo, and that inhibitors of protein kinase C (PKC) inhibited both P-glycoprotein phosphorylation and activity. However, site-directed mutagenesis of all phosphorylatable residues did not alter the drug resistance. The present work shows that PKC effectors are able to bind directly to multidrug transporters, from either cancer cells (mouse P-glycoprotein), yeast (Saccharomyces cerevisiae Pdr5p), or protozoan parasite (Leishmania tropica ltmdr1), and to inhibit their energy-dependent drug-efflux activity. The binding of staurosporine and derivatives such as CGP 41251 is prevented by preincubation with ATP, suggesting at least partial interaction at the ATP-binding site. In contrast, more hydrophobic compounds such as calphostin C and CGP 42700 bind outside the ATP-binding site and strongly interfere with drug interaction. A direct correlation is obtained between the efficiencies of PKC effectors to inhibit energy-dependent interaction of rhodamine 6G with yeast Pdr5p, to promote intracellular drug accumulation in various multidrug resistant cells, and to chemosensitize growth of resistant cells. The noncompetitive inhibition by PKC effectors of rhodamine 6G interaction with Pdr5p suggests that the binding might interfere with signal transduction between nucleotide hydrolysis and drug interaction. The overall results indicate that the multidrug transporters from different species display common features for interaction with PKC inhibitors. The hydrophobic derivative of staurosporine, CGP 42700, constitutes a potentially powerful modulator of P-glycoprotein-mediated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Ras effector-homologue region on Rac regulates protein associations in the neutrophil respiratory burst oxidase complex.

Rac, a small molecular weight GTPase in the Ras superfamily, participates in the activation of the multicomponent superoxide-generating NADPH oxidase of human neutrophils. Rac is 30% identical to Ras overall, but is 75% identical within the sequence corresponding to the effector region of Ras, which regulates mitogenesis through interactions with the protein kinase Raf1. We investigated the role of this region in Rac1 using site-directed mutagenesis. In a cell-free semirecombinant NADPH oxidase system, mutants in the 26, 33, 38, and 45 amino acids showed 20-110-fold reduced binding to the oxidase complex as judged by EC50 values and reduced (44-80%) maximal activities in superoxide generation. Only the GTP gamma S-bound form associated, since the GDP-bound form of Rac neither activated alone nor competed with GTP gamma S-Rac. EC50 values for neither p47-phox nor p67-phox were affected when mutant Racs were used in place of Rac. Data indicate direct binding of the Rac effector region to one or more components of the respiratory burst oxidase. Results indicate a general role for conserved effector-equivalent regions in small GTPases in the regulation of protein-protein interactions.

Amino Acid Sequence↗
PubMed1982

A proteolyzed derivative of Escherichia coli phosphofructokinase is no longer sensitive to allosteric effectors and still shows cooperativity in substrate binding.

Limited proteolysis of Escherichia coli phosphofructokinase by subtilisin yields a homogeneous derivative. This proteolyzed protein is composed of four polypeptide chains, with a molecular weight of 32 000 as compared to 37 000 for the original enzyme. Removal on each chain of about 5 kdaltons maintains the enzymatic activity and does not change the apparent affinity for the substrates ATP and fructose 6-phosphate. Limited proteolysis, however, affects the cooperativity of fructose 6-phosphate binding: the Hill coefficient is reduced from almost 4 in the native enzyme to only 2 in its proteolyzed derivative. Also, the proteolyzed protein is no longer sensitive to allosteric effectors, activator, or inhibitor. These changes in regulatory properties upon proteolysis are apparently due to the destruction of the effector binding site. The allosteric effector GDP protects phospho-fructokinase against proteolysis and irreversible thermal inactivation; GDP is, however, inefficient in protecting the proteolyzed protein against thermal denaturation. These results suggest that phosphofructokinase may function as a dimer of dimers, in which homotropic and heterotropic allosteric effects are not mediated by the same sets of quaternary interactions.

Adenosine Triphosphate↗
PubMed1986

Purification of a calf thymus DNA-dependent adenosinetriphosphatase that prefers a primer-template junction effector.

A purification procedure has been developed that resolves four chromatographically distinct DNA-dependent ATPase activities from calf thymus tissue. One of these activities has been purified to a nearly homogeneous protein, as judged by polyacrylamide gel electrophoresis. This protein has a specific activity of 18 mumol of ATP hydrolyzed per minute per milligram of protein and is active only in the presence of a DNA effector. The DNA-dependent ATPase activity is greatest in the presence of DNA containing a 3'-hydroxyl primer-template junction with a segment of adjacent single strand, i.e., a DNA polymerase substrate. Primer-template effectors that have had the 3'-hydroxyl group eliminated by the addition of a dideoxyribonucleotide are less active as cofactors for ATP hydrolysis than effectors which retain the 3'-hydroxyl group. Other DNAs can serve as cofactors, but with a reduced rate of ATP hydrolysis. DNA cofactors which are single stranded are much more effective at promoting ATPase activity than completely double-stranded cofactors, although the effectiveness of single-stranded DNA decreases as the length of the oligonucleotide decreases. An RNA/DNA hybrid does not promote ATPase activity. These data suggest that ATPase A may be involved in the recognition of primer-template junctions and the elongation phase of DNA synthesis.

Adenosine Triphosphatases↗
PubMed1987

Two-dimensional crystals of enzyme-effector complexes: ribonucleotide reductase at 18-A resolution.

The B1 subunit of ribonucleotide reductase formed two-dimensional crystals when bound to and effector nucleotide linked to lipids in planar layers at the air/water interface. The effector lipid consisted of dATP coupled through the gamma-phosphoryl group and an epsilon-aminocaproyl linker to phosphatidylethanolamine. Two-dimensional crystals of B1 reductase, like those of antibodies and cholera toxin obtained previously, formed under physiologic conditions of pH and ionic strength, with no precipitant added to the solution. There was, however, a requirement for dTTP in the solution, presumably to ensure binding of the dATP-lipid at only one of two effector sites on the enzyme. Diffraction from the crystals extended to 18-A resolution in negative stain, with unit cell parameters a = 110 A, b = 277 A, and gamma = 90 degrees. Image analysis revealed the B1 dimer as a pair of roughly cylindrical objects, each 105-109 A in length and 31-34 A in diameter.

Crystallization↗
PubMed1989

Dissection of the effector-binding site and complementation studies of Escherichia coli phosphofructokinase using site-directed mutagenesis.

A systematic study by site-directed mutagenesis has been conducted on the effector site of phosphofructokinase from Escherichia coli to delineate the role of side chains in binding the allosteric activator, GDP, and inhibitor, PEP, and to search for key residues in the allosteric transtion. Target residues were identified from the crystal structure of the enzyme-nucleoside diphosphate complex. It is found that both activator and inhibitor bind to the same set of amino acid side chains. Deletion of positively charged groups (Arg21, Arg25, Arg54, Arg154, and Lys213 mutated to alanine) weakens binding of both effectors by 2-3 kcal/mol, consistent with the disruption of charged hydrogen bonds. Residue Glu187, which is known from the crystal structure to bind the coordinated Mg2+ ion of GDP, is found to have a unique behavior on mutation and appears to be crucial in triggering the allosteric transition. All other residues mutated simply weaken binding of both PEP and GDP in a parallel manner. However, mutation of Glu----Ala187 reverses the roles of GDP and PEP, causing GDP to become an allosteric inhibitor and PEP an activator. Mutation of Glu----Gln187 has only a small effect on the binding of PEP, and both PEP and GDP are inhibitors. Studies are described in which mutations in different subunits of a tetrameric complex complement each other. The effector site is composed of residues from two subunits. In particular, Arg21 and Lys213 in each site are from different subunits. Mutations of either one of these residues abolishes activation by GDP of the homotetramer.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1981

Electrostatic effects in hemoglobin: electrostatic energy associated with allosteric transition and effector binding.

The pH dependence of the summed electrostatic stabilization for deoxy- and liganded hemoglobin was computed for several ionic strength values. The computed contribution to the stabilization of deoxyhemoglobin by binding of 2,3-diphosphoglycerate in the beta cleft compared well with experimental binding behavior for human hemoglobin A0 and hemoglobin F. The contribution of diphosphoglycerate binding to the alkaline Bohr effect was computed correctly for both hemoglobins A0 and F. The computed effects of simultaneous binding of diphosphoglycerate and formation of Val-1 beta carbamino adducts suggested a competition between these effectors. A direct competition was formulated between these two effectors, with extension to include a simple anion such as chloride or bicarbonate binding in competition with diphosphoglycerate but not with Val-1 beta carbamino formation. This model was found to hold at pH 7.3-7.4 over a range of concentrations of the effectors involved and to predict the pH dependence of Val-1 beta carbamino formation over the pH range 7.0-8.0. The pH dependence of the computed differential stability of liganded vs. unliganded hemoglobin A compared well with observation.

Allosteric Regulation↗
PubMed1976

Identity and properties of the chloride effector binding site in hog pancreatic alpha-amylase.

The Cl- activated alpha-amylase from mammalian sources has been shown previously to possess one Cl- binding site per molecule (Levitzki, A., and Steer, M.L. (1974), Eur. J. Biochem. 41, 171). Upon binding of the Cl- effector the kcat of the amylolytic reaction is increased 30-fold whereas the affinity toward the substrate remains unchanged. In the study presented here we have identified the Cl- binding site as a single epsilon-amino group of lysine. The pK of the unique amino group was found to be 9.1, significantly lower than the pH of a free epsilon-amino group of lysine. This epsilon-NH2 group can be blocked by a 2, 4-dinitrophenyl group upon treating the enzyme with 2, 4-dinitrofluorobenzene at pH 7.9. The dinitrophenylamylase is devoid of Cl- binding capacity but retains its substrate binding capacity. The dinitrophenylamylase also possesses the basal amylolytic activity characteristic of the unmodified Cl- free enzyme, indicating that the catalytic machinery of the enzyme is not affected by dinitrophenylation. alpha-Limit dextrins and maltose which bind to the active site protect the enzyme against dinitrophenylation at lea-st as effectively as the Cl- effector. These observations indicate that the Cl- binding lysyl residue is close to the active site and, upon binding, the Cl- effector induces an enhancement in the catalytic efficiency.

Amylases↗
PubMed2003

A model for effector activity in a highly specific biological electron transfer complex: the cytochrome P450(cam)-putidaredoxin couple.

The camphor hydroxylase cytochrome P450(cam) (CYP101) catalyzes the 5-exo hydroxylation of camphor in the first step of camphor catabolism by Pseudomonas putida. CYP101 forms a specific electron transfer complex with its physiological reductant, the Cys(4)Fe(2)S(2) ferredoxin putidaredoxin (Pdx). Pdx, along with other proteins and small molecules, has also been shown to be an effector for turnover by CYP101. Multidimensional nuclear magnetic resonance (NMR) techniques have been used to make extensive sequential (1)H, (15)N, and (13)C resonance assignments in CYP101 that permit a more complete characterization of the complex formed by CYP101 and Pdx. NMR-detected perturbations in CYP101 upon Pdx binding encompass regions of the CYP101 remote from the putative Pdx binding site, including in particular a region of the CYP101 molecule that has been implicated in substrate access to the active site via dynamical processes. A model for effector activity is proposed in which the primary role of the effector is to prevent uncoupling (formation of reduced oxo species without formation of hydroxycamphor) by enforcing conformations of CYP101 that prevent loss of substrate and/or intermediates prior to turnover. A secondary role could also be to enforce conformations that permit efficient proton transfer into the active site for coupled proton/electron transfer.

Amino Acid Sequence↗
PubMed2003

Glucosylation of Ras by Clostridium sordellii lethal toxin: consequences for effector loop conformations observed by NMR spectroscopy.

The lethal toxin (LT) from Clostridium sordellii, which belongs to the family of large clostridial cytotoxins, acts as a monoglucosyltransferase for the Rho subfamily GTPase Rac and also modifies Ras. In the present study we investigated structural changes of H-Ras in its di- and triphosphate form that occur upon glucosylation of the effector domain amino acid threonine-35 by LT. (31)P NMR experiments recorded during the enzymatic glucosylation process, using UDP-glucose as a cosubstrate, show that the modification of the threonine side chain influences the chemical shifts of the phosphate groups of the bound nucleotides. In the diphosphate-bound form (Ras.GDP) glucosylation of Thr35 induces only small changes in the chemical environment of the active center. In the triphosphate form with the GTP analogue GppNHp bound (Ras.GppNHp) Ras shows at least two different conformations in the active center that exchange on a medium-range time scale (10 to 0.1 ms). Glucosylation selectively stabilizes one distinct conformation of the effector loop (state 1) with tyrosine-32 probably apart from the nucleotide and threonine-35 not involved in magnesium ion coordination. This conformation is known to have a low affinity to effector proteins such as Raf-1, AF-6, or Byr2 and thus prevents the transduction of the activation signal in the Ras-mediated pathway. NMR correlation spectra of Ras(T35glc).GDP and denaturation experiments with urea indicate that the glucose is bound in the alpha-anomeric form to the hydroxyl group of the threonine-35 side chain. Inhibition of the glucosylation reaction by 1,5-gluconolactone suggests a stereospecific reaction mechanism with a glucosyl oxonium ion transition state for the enzymatic activity of LT.

Bacterial Toxins↗