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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have identified a new family of cytokine receptors, which is primarily characterized by the conservation of periodically interspersed four cysteine residues and the W-S-X-W-S sequence ('WS motif') within the extracellular domain. However, the role of such conserved structures still remains elusive, in particular that of the WS motif. Interleukin-2 (IL-2) is known to play a critical role in the clonal expansion of antigen-stimulated T lymphocytes, and the IL-2 signal is delivered by one of the receptor components, the IL-2 receptor beta (IL-2R beta) chain. The IL-2R beta chain, unlike the IL-2R alpha chain, belongs to this receptor family. In the present study, we analyzed the function of the WS motif of IL-2R beta (Trp194-Ser195-Pro196-Trp197-Ser198) with the use of site-directed mutagenesis. Our results indicate the critical role of the two Trp residues in the proper folding of the IL-2R beta extracellular domain and point to the general functional importance of the WS motif in the new cytokine receptor family.
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PMID:The integrity of the conserved 'WS motif' common to IL-2 and other cytokine receptors is essential for ligand binding and signal transduction. 191 91

We have cloned the IL-2 receptor gene from human genomic DNA libraries using IL-2 receptor cDNA as probe. The genomic DNA segments that hybridized with cDNA were subcloned in M13 phages and their sequences were determined. The nucleotide sequences showed that the IL-2 receptor gene was encoded by eight exons and that the coding region sequences agreed completely with that of the IL-2 receptor cDNA cloned from a cell line derived from adult T cell leukemia (ATL), in which IL-2 receptors are expressed abnormally. The nucleotide sequence of the 5'-flanking region had a putative promotor region, which had some homology with the human IL-2 gene. Transcription initiation sites were clustered about 25 bp 3' to the TATA box as assessed by primer extension analysis. These sites for normal and ATL T cells were the same. Exons 2 and 4 encoding the extracytoplasmic portion had significant homology, suggesting that the two exons are derived by duplication of an ancestral exon. Exon 2 contained six cysteine residues, four of which are conserved at the corresponding positions in exon 4.
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PMID:Molecular cloning and structure of the human interleukin 2 receptor gene. 299 98

To locate functional domains of the interleukin-2 (IL-2) protein, a cDNA clone encoding biologically active human IL-2 was mutagenized using synthetic oligonucleotides to incorporate defined amino acid substitutions and deletions in the mature protein. The IL-2 analogs were then produced in Escherichia coli and assayed for the ability to induce proliferation of IL-2-dependent cells and the ability to compete for binding to the IL-2 receptor. Our analysis of over 50 different mutations demonstrated that the integrity of at least three regions of the IL-2 molecule is required for full biological activity: the NH2 terminus (residues 1-20), the COOH terminus (residues 121-133), and 2 of the 3 cysteine residues (58 and 105). Deletion of the NH2-terminal 20 amino acids or the COOH-terminal 10 amino acids resulted in the loss of greater than 99% of bioactivity and binding. Amino acid substitutions at specific positions in these regions also resulted in proteins which retained less than 1% activity. The NH2 terminus and an adjacent internal region were recognized by neutralizing anti-IL-2 antibodies. In combination with the results from epitope competition analysis with neutralizing antibodies, these data are consistent with the IL-2 protein being folded such that the NH2 terminus, the COOH terminus, and the internal 30- to 60-region are juxtaposed to form the binding site recognized by the IL-2 receptor.
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PMID:Structure-function analysis of human interleukin-2. Identification of amino acid residues required for biological activity. 310 42

Interleukin 2 provides a signal for the proliferation and differentiation of several classes of immune cells, including activated T cells, natural killer cells and certain activated B cells. The responses to this lymphokine result from its interaction with a high-affinity cell surface receptor. Several structural features of the IL-2 molecule are essential for its functional integrity. For example, an intramolecular disulfide bridge connecting cysteine residues in positions 58 and 105 maintains an active conformation of the molecule. In addition, antibodies directed against epitopes defined by amino acids 8-27 and 33-54 are capable of directly blocking the physiological response. Amino acids in or near these regions may form part of the receptor binding site of IL-2. The receptor for IL-2 exists in both high and low-affinity states. Physiological responses correlate with binding to the high-affinity form of the receptor as determined by anti-IL-2 antibody competition curves. Expression of the cDNA corresponding to the receptor protein in mouse L cells, however, indicates that this protein alone is incapable of high-affinity interaction with IL-2. Thus, the high-affinity conformation of the receptor may entail the interaction of the ligand-binding component with an additional receptor subunit(s). The availability of pure ligand and receptor as well as antibody reagents to both these components make the IL-2 receptor system an ideal model for dissecting an immune response at the molecular level.
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PMID:Interleukin 2 and its cell-surface receptor. 393 74

Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity of NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin (TRX). As the protein tyrosine kinase activities p56lck and p59fyn are activated in intact cells by hydrogen peroxide, they are likely targets for GSSG action. These redox-regulated enzymes trigger signal cascades for NF kappa B activation and transduce signals from the T cell antigen receptor, from CD4 and CD8 molecules, and from the IL-2 receptor beta-chain. The effector phase of cytotoxic T cell responses and IL-2-dependent functions are inhibited even by a partial depletion of the intracellular GSH pool. As signal transduction is facilitated by prooxidant conditions, we propose that the well-known immunological consequences of GSH depletion ultimately may be results of the accompanying GSSG deficiency. As HIV-infected patients and SIV-infected rhesus macaques have, on the average, significantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficiency as well.
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PMID:Functions of glutathione and glutathione disulfide in immunology and immunopathology. 795 18

A soluble domain of the interleukin(IL)-2 receptor, the alpha chain synthesized in Escherichia coli, was employed to study expression and refolding of the protein. The results showed that it is possible to obtain biologically active synthetic methionine-free IL-2 receptor alpha chain (synIL-2R alpha) after BrCN cleavage and renaturation of the crude cleavage material, although the alpha chain is expressed as a deglycosylated, methionine-free protein. The soluble receptor comprises amino acids 1-219 and forms 5 disulfide bonds in its biologically active state. Biological activity has been analysed by affinity chromatography and ELISA with mutant [Ala125]IL-2 and monoclonal antibodies as ligands. Renaturation yield is limited mainly by the high aggregation rate of incorrectly folded protein. Aggregation could be limited by varying the oxidation conditions. The deletion of a non-bridging cysteine at position 192 in the synIL-2R alpha did not affect the renaturation yield of the receptor protein. Additionally a cysteine-free and methionine-free beta-galactosidase derivative was fused to the soluble synIL-2R alpha derivatives to prevent reoxidation of incorrect disulfide bonds in the crude BrCN-cleavage material. It is suggested that cysteine impurities from cyanogen-bromide-cleaved peptides might interfere seriously with the refolding process of the synthetic IL-2 receptor alpha-subunit.
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PMID:Isolation and refolding of a mutant methionine-free interleukin-2-receptor alpha chain synthesized as a fusion protein in Escherichia coli. 803 3

Injection of a low dose of mercuric chloride into Brown Norway (BN) rats caused a marked decrease in the concanavalin A (ConA)-induced generation of interferon-gamma-producing cells (IFN-gamma pc) in spleen cell cultures prepared 1 h after mercury administration. A second injection 48 h later caused a further diminution of IFN-gamma pc down to 30% of the number generated in splenocyte cultures of phosphate-buffered saline (PBS)-injected controls. Injection of Lewis rats with either one or two doses of HgCl2 revealed no inhibitory effect on splenic IFN-gamma production. The presence of the reduced form of glutathione (GSH) in the culture medium was found to be essential in these experiments. In the absence of GSH there was an overall 20-fold reduction of the number of IFN-gamma pc in splenocyte cultures of normal or PBS-injected rats, which was further reduced to a 60- to 70-fold-lower level in cultures of rats exposed to HgCl2. This mercury-mediated extra reduction could be fully reversed with an excess (2 mM) of GSH in Lewis but not in BN splenocyte cultures. Since the bivalent Hg2+ ion is known to bind to and inactivate sulfhydryl groups of proteins and low molecular weight thiols, most notably GSH, we investigated a possible role for thiols in IFN-gamma production. It was found that the generation of IFN-gamma pc in normal BN and Lewis splenocyte cultures was strongly dependent on GSH or its precursor cysteine in the culture medium. Other thiol compounds were also effective but disulfides were completely inactive. Depletion of intracellular GSH in ConA-stimulated splenocytes by buthionine sulfoximide (BSO), an inhibitor of de novo GSH biosynthesis, strongly inhibited the generation of IFN-gamma pc. The inhibitory effect of BSO was not abolished by the addition of interleukin-2 (IL-2), but was mimicked with antibodies directed to the IL-2 receptor. The data stress the importance of GSH in the enhancement of IL-2-mediated IFN-gamma production and are most consistent with a model in which mercury interferes with T cell IFN-gamma production by affecting the intracellular availability of GSH. The strain-specific susceptibility to mercury-mediated inhibition of IFN-gamma production is discussed.
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PMID:Mercuric chloride down-regulates T cell interferon-gamma production in brown Norway but not in Lewis rats; role of glutathione. 844 15

Vav has been shown to activate Ras (1-3) and is regulated by tyrosine phosphorylation (1) or binding of diglycerides (3) to the cysteine rich domain. In the present study employing different Ras activation assay techniques using [3H]GDP release or [32P]alpha GTP-binding from membrane-bound or soluble recombinant Ras, we demonstrate that Ras activity can be increased by tyrosine phosphorylated Vav upon cellular stimulation via the IL-2 receptor or the TCR/CD3-complex. Increase of [32P]alpha GTP-binding to Ras catalyzed by phosphorylated Vav is similar to the activity of immunoprecipitated Sos. The activity of Vav measured by binding of [32P]alpha GTP to Ras was linear with respect to the concentration of Vav protein used. To study molecular characteristics of this Vav-Ras interaction, we used several Ras mutants and demonstrate that Vav activity towards Ras depends on the integrity of the same or similar domains as Ras activation by SDC 25 or CDC 25.
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PMID:Molecular analysis of Ras activation by tyrosine phosphorylated Vav. 855 11

Glycyrrhizin (GL), a plant extract, has been evaluated for its inhibitory effect on HIV replication in vitro and for its improvement of clinical symptoms in HIV-infected patients. In this study, we used GL in a murine AIDS model (MAIDS) to evaluate these effects. C57BL/6 mice were inoculated with LP-BM5 murine leukemia virus to cause MAIDS. Treatment with GL supplemented with glycine and cysteine (Stronger Neo-Minophagen C, SNMC) was then begun on day 0 or 4 wks after virus inoculation. SNMC was administered three times a week for up to 19 wks. Immunological abnormalities were monitored with respect to the surface phenotype identified by two-color staining for CD3 and IL-2 receptor beta-chain. All mice infected with the virus alone developed MAIDS and died by 14 wks after infection. The immunopathogenesis was estimated to be an abnormal expansion of intermediate CD3 cells (i.e., extrathymic T cells) as well as other types of lymphocytes. SNMC did not change the total mortality rate. However, some mice that began the treatment on day 0 or 4 wks after infection survived 3 wks longer. Splenomegaly and lymphadenopathy in such mice were suppressed. These mice showed normal phenotypic features and normal responses to Con A. These results suggest that SNMC is effective in some MAIDS mice in preventing the progression of disease. When lymphocytes isolated from the liver, spleen and lymph nodes of diseased mice were cultured in vitro, they showed a spontaneous proliferation. Interestingly, such proliferation was inhibited by addition of liver lymphocytes, but not splenic lymphocytes, obtained from normal or SNMC-treated mice. Since liver lymphocytes contains intermediate CD3 cells with autoreactivity, they may possibly suppress the progression of disease.
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PMID:Therapeutic effects of glycyrrhizin in mice infected with LP-BM5 murine retrovirus and mechanisms involved in the prevention of disease progression. 901 40

Growing evidence has indicated that cellular reduction/oxidation (redox) status regulates various aspects of cellular function. Oxidative stress can elicit positive responses such as cellular proliferation or activation, as well as negative responses such as growth inhibition or cell death. Cellular redox status is maintained by intracellular redox-regulating molecules, including thioredoxin (TRX). TRX is a small multifunctional protein that has a redox-active disulfide/dithiol within the conserved active site sequence: Cys-Gly-Pro-Cys. Adult T cell leukemia-derived factor (ADF), which we originally defined as an IL-2 receptor alpha-chain/Tac inducer produced by human T cell lymphotrophic virus-I (HTLV-I)-transformed T cells, has been identified as human TRX. TRX/ADF is a stress-inducible protein secreted from cells. TRX/ADF has both intracellular and extracellular functions as one of the key regulators of signaling in the cellular responses against various stresses. Extracellularly, TRX/ADF shows a cytoprotective activity against oxidative stress-induced apoptosis and a growth-promoting effect as an autocrine growth factor. Intracellularly, TRX/ADF is involved in the regulation of protein-protein or protein-nucleic acid interactions through the reduction/oxidation of protein cysteine residues. For example, TRX/ADF translocates from the cytosol into the nucleus by a variety of cellular stresses, to regulate the expression of various genes through the redox factor-1 (Ref-1)/APEX. Further studies to clarify the regulatory roles of TRX/ADF and its target molecules may elucidate the intracellular signaling pathways in the responses against various stresses. The concept of "redox regulation" is emerging as an understanding of the novel mechanisms in the pathogenesis of several disorders, including viral infections, immunodeficiency, malignant transformation, and degenerative disease.
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PMID:Redox regulation of cellular activation. 914 92


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