Disease relevance of CPR1

• This suggests that the CYP1 gene product is the primary cellular target for CsA toxicity in yeast [1].
• Structure and expression of cytosolic cyclophilin/peptidyl-prolyl cis-trans isomerase of higher plants and production of active tomato cyclophilin in Escherichia coli [2].
• Interestingly the B. subtilis PPIase shows about 40% identity to eukaryotic PPIases and less similarity to those of Gram-negative bacteria (27-32% identity) [3].
• Sequencing of N-terminal and internal peptide fragments of the purified 17 kDa Bacillus subtilis peptidyl-prolyl cis-trans isomerase (PPIase) revealed sequence identity to conserved regions of a number of eukaryotic and prokaryotic cyclophilins [3].
• A Candida albicans cDNA and its genomic counterpart were isolated from lambda phage libraries using a human T-cell cyclophilin (Cyp) cDNA as a hybridization probe [4].

High impact information on CPR1

• Calcineurin is potently inhibited by immunosuppressant drugs, cyclosporin A and FK506, in the presence of their respective cytoplasmic immunophilin proteins, cyclophilin and FK506-binding protein [5].
• Pin1 is thus an essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity [6].
• Peptidyl-prolyl cis-trans isomerase (PPIase) catalyses the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and has been shown to accelerate the refolding of several proteins in vitro [7].
• Thus we propose that the peptidyl-prolyl cis-trans isomerizing activity of PPIase may be involved in events, such as those occurring early in T-cell activation, that are suppressed by cyclosporin A [7].
• The biochemical basis of CsA action is not known: its primary cellular target has been suggested to be calmodulin, the prolactin receptor or cyclophilin, a CsA-binding protein originally isolated from the cytosol of bovine thymocytes [8].

Chemical compound and disease context of CPR1

• The peptidyl-prolyl cis-trans isomerases cyclophilin A and FKBP12, respectively, mediate CsA and FK506 toxicity in the cev1 mutant strain [9].
• 7. From these characteristics, CP2/PCB can be attributed to the Pr" photochemical type with gamma1 < or = 0.05, which comprises the minor phyA fraction (phyA"), phyB, Adiantum phy1 and Synechocystis Cph1 in contrast to the major phyA' fraction (Pr' type with gamma1 = 0.5) [10].

Biological context of CPR1

• Unable to identify a phenotype that is suggestive of Cpr1p's function in a cpr1Delta Saccharomyces cerevisiae strain, we screened for CPR1-dependent strains [11].
• Cyclophilins have in vitro peptidylprolyl cistrans isomerase (PPIase) activity, and thus may be involved in protein folding in vivo [12].
• A yeast cyclophilin gene essential for lactate metabolism at high temperature [12].
• Cyclophilin A peptidyl-prolyl isomerase activity promotes ZPR1 nuclear export [11].
• Using a degenerate oligodeoxyribonucleotide (oligo) based on the N-terminal aa sequence, plus an internal oligo homologous to a conserved region within the portion of CYP1 and CYP2 that had been deleted in the genome, a CYP3-specific DNA fragment was generated by the polymerase chain reaction (PCR) using GL81 genomic DNA as a substrate [13].

Anatomical context of CPR1

• The immunosuppressants FK506 and cyclosporin A (CsA) bound to their receptors, FKBP12 or cyclophilin, inhibit the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, preventing T cell activation or, in yeast, recovery from alpha-mating factor arrest [14].
• Cyclophilin catalyzes protein folding in yeast mitochondria [15].
• While the majority of this protein is sequestered in insoluble inclusion bodies, the soluble extracts have higher levels of peptidyl-prolyl cis-trans isomerase (rotamase) activity than extracts of wild-type cells [2].
• The CYP1-encoded protein was not required to target proteins to peroxisomes because this organelle appeared to be assembled normally in a CYP1-disrupted strain [16].
• Therefore, the combined activities of Cph1p and Efg1p are required for C. albicans to stimulate a proinflammatory response in endothelial cells [17].

Associations of CPR1 with chemical compounds

• The immunosuppressant and cytotoxic effects of CsA are thought to result from formation of a toxic complex between cyclophilin and CsA rather than from inhibition of cyclophilin function [12].
• The CYP2 gene of Saccharomyces cerevisiae encodes a cyclosporin A-sensitive peptidyl-prolyl cis-trans isomerase with an N-terminal signal sequence [1].
• Improvement of flavone biosynthesis was achieved by overexpressing the yeast P450 reductase CPR1 in the FSII-expressing recombinant strain and by using acetate rather than glucose or raffinose as the carbon source [18].
• Expression of human oxidoreductase complemented a mutation in the yeast oxidoreductase gene CPR1 and fully reversed the ketoconazole sensitive phenotype of the respective strain [19].
• Multiple signaling pathways, including a Cph1-mediated mitogen-activated protein kinase pathway and an Efg1-mediated cyclic AMP/protein kinase A pathway, regulate the transition [20].

Physical interactions of CPR1

• By affinity chromatography, both FKBP12 and cyclophilin A bind calcineurin A in the absence of ligand, and FK506 and cyclosporin A respectively potentiate these interactions [21].

Regulatory relationships of CPR1

• The levels of Cpr1p were reduced in the Deltavid22 mutants, implying that the expression of Cpr1p is regulated by Vid22p [22].
• When ammonium is absent or present at low concentrations, Mep2p activates both the Cph1p-dependent mitogen-activated protein (MAP) kinase pathway and the cAMP-dependent signalling pathway in a Ras1p-dependent fashion via its C-terminal cytoplasmic tail, which is essential for signalling but dispensable for ammonium transport [23].

Other interactions of CPR1

• We have isolated a yeast cyclophilin gene, CPR3, which encodes a presumptive mitochondrial isoform [12].
• Furthermore, the addition of purified Cpr1p restored FBPase import in both the Deltacpr1 and the Deltavid22 mutants [22].
• RPA14 is a single copy gene that maps to chromosome IV and is flanked by CYP1 and HOM2 [24].
• Our results suggest that Cpr1p mediates Vid22p function and is directly involved in the import of FBPase into Vid vesicles [22].
• Crosstalk of prolyl isomerases, Pin1/Ess1, and cyclophilin A [25].

Analytical, diagnostic and therapeutic context of CPR1

• On the basis of the result of SDS-PAGE, PPI-II and PPI-III were highly purified and their molecular masses were estimated to be 16.5 and 17.2 kDa, respectively [26].
• Southern-blot analysis of yeast DNA shows that only one CPH-related sequence is present per haploid genome, whereas at least 20 genes or pseudogenes were detected in the human and rat genome [27].
• We applied two-dimensional gel electrophoresis to identify downstream effectors of CPH1 and EFG1 under hypha-inducing conditions in Candida albicans [28].
• In these conditions, the CYP1 protein is detected by Western blot analysis and has a molecular mass in agreement with the open reading frame sequence [29].
• Substitution in position 3 of cyclosporin A abolishes the cyclophilin-mediated gain-of-function mechanism but not immunosuppression [30].

References