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. 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. Several reports indicate that CsA has potent anti-parasitic activity, effective against both protozoan and helminth species. In order to understand the various biological roles that cyclophilins play we have initiated a study of these proteins in the genetically tractable nematode Caenorhabditis elegans. Here we describe the cloning and characterization of 11 cyclophilin genes (cyp-1 to -11) derived from this nematode; this is currently the greatest number of isoforms described in a single species. Southern blotting and physical mapping indicated that these genes are dispersed throughout the nematode genome. A high degree of conservation exists between several isoforms, which also share characteristics with the ubiquitous isoforms previously described. The remaining isoforms are divergent, having altered CsA-binding domains and additional non-cyclophilin domains, which may impart compartmental specificity. Ten of these isoforms have been expressed in Escherichia coli, and the resultant fusion proteins have been examined biochemically for PPI activity, which they all possess. Isomerase activity is highest in the conserved and lowest in divergent isoforms, perhaps indicating a more specific substrate for the latter. Analysis of the C. elegans cyp genes will provide answers as to the roles played by cyclophilins in protein folding and signal transduction.
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July 1996
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Research Article|
July 01 1996
Cloning and biochemical characterization of the cyclophilin homologues from the free-living nematode Caenorhabditis elegans
Antony P. PAGE;
Antony P. PAGE
‡
*Wellcome Unit of Molecular Parasitology, The Anderson College, Glasgow University, Glasgow G11 6NU, Scotland, U.K.
‡To whom correspondence should be addressed.
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Kenneth MacNIVEN;
Kenneth MacNIVEN
*Wellcome Unit of Molecular Parasitology, The Anderson College, Glasgow University, Glasgow G11 6NU, Scotland, U.K.
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Michael O. HENGARTNER
Michael O. HENGARTNER
†Cold Spring Harbor Laboratory, P.O. Box 100, Cold Spring Harbor, New York 11724, U.S.A.
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Publisher: Portland Press Ltd
Received:
December 22 1995
Accepted:
February 27 1996
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 317 (1): 179–185.
Article history
Received:
December 22 1995
Accepted:
February 27 1996
Citation
Antony P. PAGE, Kenneth MacNIVEN, Michael O. HENGARTNER; Cloning and biochemical characterization of the cyclophilin homologues from the free-living nematode Caenorhabditis elegans. Biochem J 1 July 1996; 317 (1): 179–185. doi: https://doi.org/10.1042/bj3170179
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