Peptidylproline cis‐trans‐isomerases: immunophilins

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Abstract
Two sequence‐unrelated families of proteins possess peptidylproline cis‐trans‐isomerase activities (PPlase). PPlases are highly sequence conserved and multifunctional proteins which are present in many types of cells with a considerably divergent phylogenetic distribution. On the cellular level, PPlases occur in every compartment, both as free species and anchored to membranes. Diverse posttranslational modifications such as glycosylation, N‐terminal modifications and phosphorylation constitute the additional functional features of PPlase. Folding, assembly and trafficking of proteins in the cellular milieu are regulated by PPlase. These enzymes accelerate the rate of in‐vitro protein folding and they have the ability to bind proteins and act as chaperones. Some PPlases are coregulatory subunits of molecular complexes including heat‐shock proteins, glucocortcoid receptors and ion channels. Secreted forms of PPlases are inflammatory and chemotactic agents for monocytes, eosinophils and basophils. The potent and clinically useful immunosuppressants CsA, FK506 or rapamycin bind with high affinities to PPlases (immunophilins). The binding criterion allows us to sort the PPlases for the following two superfamilies of proteins: the cyclophilins (CsA‐binding proteins) and the FKBP (FK506/rapamycin‐binding proteins).Although none of PPlases appeared to be essential for the viability of haploid yeast cells some of the immunophilin/immunosuppressant complexes are toxic both for yeast and mammalian cells. At least seven unlinked genes of cyclophilins and four unlinked genes of FKBP exist in human genomic DNA. Selected immunophilins regulate two different signalling pathways in lymphoid cells, namely the secretion of growth factors by stimulated T‐cells and interleukin‐2‐induced T‐cell proliferation. Moreover, selected FKBP mediate the cytotoxic effects of rapamycin in non‐lymphoid cells. Accounts of the discovery of PPlases (immunophilins) and their functions are given in this review. A larger spectrum of proteins is analysed in relation to various signal‐transduction pathways in lymphoid cells which involve immunophilins or their complexes with the immunosuppressants CsA, FK506 or rapamycin.