The cyclophilins

Abstract

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.

Figure 1

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 interconversion between the two forms is catalyzed by cyclophilins and other peptidyl-prolyl isomerases (PPIases) [7]. The carbon atoms of the proline are indicated by Greek letters; P₂ indicates a third amino acid on the other side of the proline. The peptide bond has some double-bond character and is planar.

Figure 2

The structure of the ternary complex between the drug cyclosporin A (CsA), human cyclophilin A (CypA) and human calcineurin [37]. The CsA-CypA binary complex lies at the base of the helical arm of the catalytic subunit of calcineurin (CnA) that binds the regulatory subunit calcineurin (CnB); it nestles in a hydrophobic groove in intimate contact with both subunits, at a region unique to calcineurin and not found in other phosphatases, and this intimate contact gives the interaction high specificity. Reproduced with permission from [37].

Figure 3

Primary structures, localizations and mammalian orthologs of S. cerevisiae cyclophilins [6]. Abbreviations: CLD, cyclophilin-like domain; ER, ER retention signal; M, mitochondrial localization signal; SP, signal peptide; TM, transmembrane domain; TPR, tetratricopeptide repeat.