Disease relevance of cyclophilin

• A divergent multi-domain cyclophilin from the filarial nematodes Brugia malayi, Onchocerca volvulus and Dirofilaria immitis has a highly conserved orthologue in the free-living nematodes Caenorhabditis elegans and C. briggsae [1].

High impact information on cyclophilin

• Thirdly, we find that each of six genes, mog-1-mog-6, is required for repression by the fem-3 3' UTR [2].
• The switch from spermatogenesis to oogenesis in the Caenorhabditis elegans hermaphrodite requires mog-6, which post-transcriptionally represses the fem-3 RNA [3].
• Finally, we found that gld-3 mog-6 mutants develop germline tumors, suggesting that mog-6 might function in the decision between mitosis and meiosis [3].
• A highly diversified member of the cyclophilin family of peptidyl-prolyl cis-trans isomerases has been isolated from the human parasite Onchocerca volvulus (OvCYP-16) [4].
• Cyclophilin 3 (CYP-3) is one of the most abundantly expressed cyclophilin isoforms in the free living nematode Caenorhabditis elegans [5].

Biological context of cyclophilin

• Cyclosporin A (CsA) is the most widely used immunosuppressive agent, whose properties are exerted via an interaction with cyclophilin, resulting in down-regulation of signal-transduction events in the T-cell [6].
• A divergent multi-domain cyclophilin is highly conserved between parasitic and free-living nematode species and is important in larval muscle development [1].
• Interestingly, the active site pocket is occupied by a molecule of dithiothreitol though this has little effect on the geometry of the active site which is similar to other cyclophilin structures [7].
• During the large-scale sequencing analysis of a human fetal brain cDNA library, we isolated two cDNA clones encoding two novel proteins, which show 52% and 72% identity to the cyclophilin isoform 10 of C. elegans, respectively [8].
• The genomes of Drosophila melanogaster, Caenorhabditis elegans, Arabidopsis thaliana, Schizosaccharomyces pombe, and Saccharomyces cerevisiae encode different numbers of the cyclophilin paralogues, some of which are orthologous to the human cyclophilins [9].

Anatomical context of cyclophilin

• In mog-2-mog-6 mutants, spermatogenesis continues past the time at which hermaphrodites normally switch into oogenesis and no oocytes are observed [10].
• The cyp-4 transcript is most abundantly expressed in the early larval stages and is expressed exclusively in the body-wall striated muscle cells [1].

Associations of cyclophilin with chemical compounds

• The remaining isoforms are divergent, having altered CsA-binding domains and additional non-cyclophilin domains, which may impart compartmental specificity [6].
• Cyclophilin is identical with peptidylprolyl cis-trans isomerase (PPI; EC 5.2.1.8), an enzyme which catalyses the isomerization between the two proline conformations in proteins, thereby acting as a catalyst in protein-folding events [6].

Regulatory relationships of cyclophilin

• We further speculate that the mog-1-mog-6 mutations all interfere with translational controls of fem-3 and other maternal mRNAs [10].

Other interactions of cyclophilin

• We propose that the mog-2-mog-6 mutations identify genes that act with mog-1 to effect the sperm/oocyte switch [10].
• Analyses of mog;fem-3 double mutants suggest that the mog-2-mog-6 genes act before fem-3; thus these genes may be in a position to negatively regulate fem-3 or one of the other terminal regulators of germline sex determination [10].
• In this paper, we report the genetic identification of five genes, mog-2, mog-3, mog-4, mog-5, and mog-6, that influence the hermaphrodite switch from spermatogenesis to oogenesis [10].

Analytical, diagnostic and therapeutic context of cyclophilin

• Sequence analysis revealed these two cDNA clones are two different splicing variants of a novel cyclophilin-like gene (PPIL3) [8].

References