Immunophilins: switched on protein binding domains?

Peptidylprolyl isomerases (PPIases) are a group of cytosolic enzymes first characterized by their ability to catalyze the cis-trans isomerization of cis-peptidylprolyl bonds. Subsequently, some PPIases were also identified as the initial targets of the immunosuppressant drugs-cyclosporin A (CsA), FK506, and rapamycin-have been called immunophilins. Immunophilins have been found to be both widely distributed and abundantly expressed leading to suggestions that they may play a general role in cellular biochemistry. However, the nature of this role has been difficult to elucidate and is still controversial in vivo. A number of roles for these enzymes have been identified in vitro including the ability to catalyze the refolding of partly denatured proteins and stabilize multiprotein complexes such as Ca(2+) channels, inactive steroid receptor complexes, and receptor protein tyrosine kinases. Generally, these effects appear to depend on the ability of immunophilins to selectively bind to other proteins. This review will examine in detail experimental and structural investigations of the mechanism of PPIase activity for both FKBPs and cyclophilins and suggest a mechanism for these enzymes, which depends on their ability to recognize a specific peptide conformation rather than sequence. Examination of structures of immunophilin-protein complexes will then be used to further suggest that the ability of these enzymes to recognize specific peptide conformations is central to the formation of these complexes and may constitute a general function of immunophilin enzymes. The binding of ligand to immunophilins will also be shown to stabilize specific conformations in surface loops of these proteins that are observed to play a critical role in a number of immunophilin-protein complexes suggesting that the immunophilins may constitute a class of ligand-triggered selective protein binders.