Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunophilins are protein chaperones with peptidylprolyl isomerase activity that belong to one of two large families, the cyclosporin-binding cyclophilins (CyPs) and the FK506-binding proteins (FKBPs). Each family displays characteristic and conserved sequence features that differ between the two families. We report a novel group of dual-family immunophilins that contain both CyP and FKBP domains for which we propose the name FCBP (FK506- and cyclosporin-binding protein). The FCBP of Toxoplasma gondii, a protozoan parasite, contained N-terminal FKBP and C-terminal CyP domains joined by tetratricopeptide repeats. Structure-function analysis revealed that both domains were functional and exhibited family-specific drug sensitivity. The individual domains of FCBP inhibited calcineurin (protein phosphatase 2B) in the presence of the appropriate drugs. In binding studies, FCBP recruited calcineurin in the presence of FK506 and a putative target of rapamycin homolog in the presence of rapamycin. Two additional FCBP sequences in Flavobacterium and one in Treponema (spirochete) were also identified in which the CyP and FKBP domains were in the reverse order. T. gondii growth was inhibited by cyclosporin and FK506 in a moderately synergistic manner. The knockdown of FCBP by RNA interference revealed its essentiality for T. gondii growth. Clearly, the FCBPs are novel chaperones and potential targets of multiple immunosuppressant drugs.
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PMID:A novel class of dual-family immunophilins. 1584 46

Cyclophilins (Enzyme Commission (EC) number 5.1.2.8) belong to a group of proteins that have peptidyl-prolyl cis-trans isomerase activity; such proteins are collectively known as immunophilins and also include the FK-506-binding proteins and the parvulins. Cyclophilins are found in all cells of all organisms studied, in both prokaryotes and eukaryotes; humans have a total of 16 cyclophilin proteins, Arabidopsis up to 29 and Saccharomyces 8. The first member of the cyclophilins to be identified in mammals, cyclophilin A, is the major cellular target for, and thus mediates the actions of, the immunosuppressive drug cyclosporin A. Cyclophilin A forms a ternary complex with cyclosporin A and the calcium-calmodulin-activated serine/threonine-specific protein phosphatase calcineurin; formation of this complex prevents calcineurin from regulating cytokine gene transcription. Recent studies have implicated a diverse array of additional cellular functions for cyclophilins, including roles as chaperones and in cell signaling.
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PMID:The cyclophilins. 1599 57

Hensin is a rabbit ortholog of DMBT1, a multifunctional, multidomain protein implicated in the regulation of epithelial differentiation, innate immunity, and tumorigenesis. Hensin in the extracellular matrix (ECM) induced morphological changes characteristic of terminal differentiation in a clonal cell line (clone C) of rabbit kidney intercalated cells. Although hensin is secreted in monomeric and various oligomeric forms, only the polymerized ECM form is able to induce these phenotypic changes. Here we report that hensin secretion and matrix assembly were inhibited by the peptidylprolyl cis-trans isomerase (PPIase) inhibitors cyclosporin A (CsA) and a derivative of cyclosporin A with modifications in the d-Ser side chain (Cs9) but not by the calcineurin pathway inhibitor FK506. PPIase inhibition led to failure of hensin polymerization in the medium and ECM, plus the loss of apical cytoskeleton, apical microvilli, and the columnar epithelial shape of clone C cells. Cyclophilin A was produced and secreted into the media to a much greater extent than cyclophilins B and C. Our results also identified the direct CsA-sensitive interaction of cyclophilin A with hensin, suggesting that cyclophilin A is the PPIase that mediates the polymerization and matrix assembly of hensin. These results are significant because this is the first time a direct role of peptidylprolyl cis-trans isomerase activity has been implicated in the process of epithelial differentiation.
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PMID:Secreted cyclophilin A, a peptidylprolyl cis-trans isomerase, mediates matrix assembly of hensin, a protein implicated in epithelial differentiation. 1911 4

Cyclophilin A (CypA) is a ubiquitous cis-trans prolyl isomerase with key roles in immunity and viral infection. CypA suppresses T-cell activation through cyclosporine complexation and is required for effective HIV-1 replication in host cells. We show that CypA is acetylated in diverse human cell lines and use a synthetically evolved acetyllysyl-tRNA synthetase/tRNA(CUA) pair to produce recombinant acetylated CypA in Escherichia coli. We determined atomic-resolution structures of acetylated CypA and its complexes with cyclosporine and HIV-1 capsid. Acetylation markedly inhibited CypA catalysis of cis to trans isomerization and stabilized cis rather than trans forms of the HIV-1 capsid. Furthermore, CypA acetylation antagonized the immunosuppressive effects of cyclosporine by inhibiting the sequential steps of cyclosporine binding and calcineurin inhibition. Our results reveal that acetylation regulates key functions of CypA in immunity and viral infection and provide a general set of mechanisms by which acetylation modulates interactions to regulate cell function.
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PMID:Acetylation regulates cyclophilin A catalysis, immunosuppression and HIV isomerization. 2036 29

Cyclosporin A (CsA) is an immunosuppressant drug widely used in organ transplant recipients and people with autoimmune disorders. Long term treatment with CsA is associated with many side effects including hyperlipidemia and an increased risk of atherosclerosis. While its immunosuppressive effects are closely linked to its effects on T cell activation via the inhibition of the nuclear factor of activated T cells (NFAT) pathway, the precise mechanisms underlying its cardiovascular effects appear to involve multiple pathways additional to those relevant for immunosuppression. These include inhibition of calcineurin activity and intracellular cyclophilin peptidylprolyl isomerase and chaperone activities, inhibition of pro-inflammatory extracellular cyclophilin A, and NFAT-independent transcriptional effects. CsA demonstrates complex effects on lipoprotein metabolism and bile acid production, and affects endothelial cells, smooth muscle cells and macrophages, all of which are critical to the atherosclerotic process. Interpretation of the available data is hampered as many experimental models are used to study the effects of CsA in vivo and in vitro, leading to diverse and often contradictory findings. In this review we will describe the cellular mechanisms related to CsA-induced hyperlipidemia and atherosclerosis, with a focus on identifying pro-atherogenic pathways that are distinct from those relevant to its immunosuppressant effects. The potential of CsA analogues to avoid such sequelae will be discussed.
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PMID:Cyclosporin A and atherosclerosis--cellular pathways in atherogenesis. 2059 51

Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo- to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses.
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PMID:Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1. 2232 60

Microorganisms evolve via a range of mechanisms that may include or involve sexual/parasexual reproduction, mutators, aneuploidy, Hsp90 and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show that the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidylprolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild-type phenotype when grown without exposure to the drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNAs and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves the generation of a double-stranded RNA trigger intermediate using the fkbA mature mRNA as a template to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes.
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PMID:Antifungal drug resistance evoked via RNAi-dependent epimutations. 2507 29

Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to HIV-derived lentiviral vectors (LVs) remains a challenge for the field of gene therapy as high vector doses and prolonged ex vivo culture are still required to achieve clinically relevant transduction levels. We report here that Cyclosporin A (CsA) and Rapamycin (Rapa) significantly improve LV gene transfer in human and murine HSPC. Both compounds increased LV but not gammaretroviral transduction and acted independently of calcineurin and autophagy. Improved gene transfer was achieved across all CD34(+) subpopulations, including in long-term SCID repopulating cells. Effects of CsA were specific of HSPC and opposite to its known impact on HIV replication. Mutating the Cyclophilin A binding pocket of the viral capsid (CA) further improved transduction in combination with CsA. Tracking of the LV genome fate revealed that CsA relieves a CA-dependent early block and increases integration, while Rapa acts early in LV infection independently of the viral CA. In agreement, only Rapa was able to improve transduction by an integrase-defective LV harboring wild-type CA. Overall, our findings pave the way for more efficient and sustainable LV gene therapy in human HSPCs and shed light on the multiple innate barriers specifically hampering LV transduction in these cells.
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PMID:Cyclosporin a and rapamycin relieve distinct lentiviral restriction blocks in hematopoietic stem and progenitor cells. 2527 76

Marine sponges are found to be a wide source of bioactive compounds with different effects such as anti-inflammatory or anticancer actions among others. Cyclophilin A (Cyp A) is a target protein implicated in the mechanism of action of immunosuppressive compounds such as Cyclosporine A (CsA). In the present paper we studied the binding between 4 Spongionella compounds (Gracilins H, A, L and Tetrahydroaplysulphurin-1) and Cyp A immobilized over a CM5 sensor chip. Thus, we found that Spongionella compounds showed to have similar binding affinities than CsA with dissociation equilibrium constant in the range. Next, the effect of these Spongionella isolated compounds was tested over calcineurin phosphatase activity. The same than CsA, Gracilin H, A and Tetrahydroaplysulphurin-1 were able to inhibit phosphatase activity once the complex between Cyp A-CsA/Spongionella compounds was formed. The ability to avoid the dephosphorylation of NFATc1 was also checked in human T cells isolated from peripheral blood. First, cells were pre-treated with Spongionella compounds or CsA following by Concanavalin A (Con A) stimulation. In these conditions nuclear NFATc1 levels were diminished either by CsA or Gracilin A, L, and Tetrahydroaplysulphurin-1 treatment. Moreover, as happens with CsA due to the inhibition of NFATc1, Interleukine-2 (IL-2) released to the culture medium was significantly decreased with all Spongionella compounds. Results conclude that, Spongionella derivatives preserve T lymphocytes from activation modulating the same pathway than CsA. Thus, this mechanism of action suggests that these compounds could be interesting candidates in drug development as immunosuppressive or anti-inflammatory drugs.
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PMID:Identification of Spongionella compounds as cyclosporine A mimics. 2704 81


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