Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressive drug cyclosporin A (CsA) inhibits the growth of malaria parasites in vitro and in vivo. Cyclosporin A exerts its immunosuppressive effect in T lymphocytes by binding to cyclophilin (CyP), a peptidylprolyl cis-trans isomerase (PPIase). It is believed that the cyclosporin/cyclophilin complex inhibits a Ca(2+)-activated protein phosphatase, calcineurin, involved in T-cell activation. A cDNA encoding a cyclophilin of the human malaria parasite Plasmodium falciparum has been isolated as a step in the elucidation of the mechanism of antimalarial action of CsA. This cDNA, termed PfCyP, encodes a protein of 195 amino acids which has highest similarity with the Candida albicans (73.1%) and the Drosophila melanogaster (73.1%) cytoplasmic cyclophilins. A Northern blot reveals an approximately 900-bp nucleotide transcript that is consistent with the predicted size of the encoded polypeptide. The predicted PfCyP protein has a putative endoplasmic-reticulum-directed signal sequence at its N-terminus and two potential N-linked glycosylation sites. Expression of PfCyP RNA in an in vitro translation/translocation system reveals that the PfCyP protein is translocated across microsomes, that the signal peptide is cleaved and that the PfCyP protein is glycosylated at two sites. The PfCyP cDNA open reading frame coding for the predicted mature protein has been expressed in Escherichia coli. The purified recombinant protein is an active PPIase (kcat/Km = 2.3 x 10(6) s-1 M-1); this enzymic activity is inhibited by CsA (IC50 = 10 nM). The PfCyP protein has thus the same sensitivity to CsA as the PPIase activity associated with P. falciparum extracts [Bell, A. et al. (1994) Biochem. Pharmacol. 48, 495-503] suggesting that PfCyP may be responsible for the PPIase activity in those extracts. If different cyclophilins exist in P. falciparum, we conclude that either the PfCyP protein is the major cyclophilin detected in the parasite or that there are other cyclophilins with similar susceptibilities to CsA.
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PMID:Molecular and biochemical characterization of a Plasmodium falciparum cyclophilin containing a cleavable signal sequence. 758 14

A novel inositolphosphate-binding protein has been identified and shown to be an immunophilin. This protein, which was isolated from human erythrocyte membranes and from K562 (human erythroleukemia) cell membranes, has robust peptidylprolyl cis-trans isomerase activity that is strongly inhibited by nanomolar concentrations of FK506 or rapamycin, indicating a member of the FKBP (FK506-binding protein) class. However, unlike the cytosolic FKBP12, the isomerase activity of this membrane-associated immunophilin is strongly inhibited by nanomolar concentrations of inositol 1,4, 5-trisphosphate (IP(3)), inositol 1,3,4,5-tetrakisphosphate (IP(4)), and phosphatidylinositol 4- and 4,5-phosphates, which are suggested to be physiological ligands. The demonstration of a single 12-kD protein that binds both IP(4) or IP(3) and anti-FKBP12 provides strong support for the inositolphosphate-binding immunophilin having an apparent mass of 12 kD, and it is suggested that the protein might be called IPBP12 for 12-kD inositol phosphate binding protein. When an internal tryptic peptide derived from IPBP12 was sequenced, a sequence also present in human cytokeratin 10 was identified, suggesting a cytoskeletal localization for the immunophilin. While purifying IPBP12, it was found that it is immunoprecipitated with specific proteins that include a protein kinase and a phosphoprotein phosphatase. The latter is indicated to be phosphoprotein phosphatase 2A (PP-2A). It is suggested that immunophilins promote the assembly of multiprotein complexes that often include a protein kinase or a phosphoprotein phosphatase or both.
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PMID:An inositolphosphate-binding immunophilin, IPBP12. 1051 81

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