Protein family review
This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.
Authors:
1The Research Institute for Children, Children's Hospital, and Departments of Pediatrics, and Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70118, USA
2Departments of Molecular Genetics and Microbiology, Medicine, and Pharmacology and Cancer Biology and the Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA
Correspondence:
Ping Wang
Email:
pwang@lsuhsc.edu
Read the full article
Subscribers to GenomeBiology may view the full version of this review article online at www.genomebiology.com
Published:
27 June 2005
The cyclophilins
Summary
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.
Frontiers
Recent studies have suggested a new role for cyclophilins in cell signaling. For example, mammalian CypA has been found to regulate the T-cell-specific interleukin-2 tyrosine kinase Itk, which contains conserved Src homology 2 (SH2), Src homology 3 (SH3), and kinase domains [63-65]. Itk is a non-receptor protein-tyrosine kinase that has a role in the maturation of thymocytes and is required for intracellular signaling events leading to T-cell activation. Binding of CypA to the SH2 domain of Itk results in conformational change within the SH2 domain that alters ligand specificity [63]. Mutation of a proline residue in the SH2 domain disrupts the interaction between Itk and CypA and specifically increases the production of type 2 (Th2) cytokines (cytokines produced by Th2 helper cells) [65,66].
In another example of a cyclophilin involved in cell signaling, human CypB has been found to govern the activation of interferon-regulatory factor-3 (IRF-3). IRF-3 is a member of the group of interferon regulatory factors that induce interferon-β once translocated into the nucleus. CypB interacts with IRF-3 in the yeast two-hybrid assay. An RNA-interference study of CypB indicates that the suppression of virus-induced IRF-3 phosphorylation and other related events can result in the inhibition of interferon-1β [67].
Finally, the mitochondrially targeted cyclophilin CypD has been found to play an important role in the mitochondrial permeability transition, in which mitochondrial pores open, leading to cell death [68-72]. By generating CypD-deficient mice, several research groups have discovered that CypD and the mitochondrial permeability transition are required to mediate the cell death induced by calcium and oxidative damage, but not to mediate conventional apoptosis involving Bcl-2 family proteins [70-72]. Further exploration of the role of CypD in mitochondrial function and its potential as a novel drug target has been also discussed recently [8].
© BioMedCentral Ltd. Protein family reviews appear as regular features in GenomeBiology. A complete list of protein family reviews is available online at http://genomebiology.com/proteinfamilyreviews/
A schematic illustration of the trans and cis isomers of the peptide bond between proline (on the left of each structure shown) and another amino acid (P1, on the right)
The structure of the ternary complex between the drug cyclosporin A (CsA), human cyclophilin A (CypA) and human calcineurin [37]
Primary structures, localizations and mammalian orthologs of S. cerevisiae cyclophilins [6]