The immunophilins

Summary

The structurally unrelated drugs cyclosporin A (CsA) and FK-506 are powerful immunosuppressants, used prophylactically following transplant surgery to prevent organ rejection. Although neither drug was originally identified by a mechanism-based screen, these extraordinarily effective immunosuppressants have become important tools for understanding T-lymphocyte activation. Both drugs bind to receptors that have been given the generic name immunophilins to describe immunosuppressant binding proteins. The immunophilins are divided into two distinct families, based upon their binding specificity for drug and upon their amino acid sequence similarity. The CsA binding proteins are termed cyclophilins (CyPs) and the FK-506 binding proteins have been given the acronym FKBP. The FKBPs also bind rapamycin, an immunosuppressant structurally related to FK-506 [1], but which has a biochemical mechanism of action distinct from that of CsA and FK-506. CsA and FK-506 are inactive alone and are more aptly described as co-drugs that must first bind to their cognate immunophilin to form the active immunosuppressive species. Surprisingly, since the structures of the drugs are different and the two immunophilin families are unrelated phylogenetically, both drug-immunophilin complexes converge upon protein phosphatase 2B, calcineurin (CaN), a key regulatory component of the T-cell activation pathway. Immunosuppression results from inhibition of CaN phosphatase activity. Both classes of immunophilins are themselves enzymes which catalyze the cis-to-trans isomerization of Xaa-Pro amide bonds (peptidyl-prolyl isomerase or PPI) in polypeptides and proteins. The enzymology of the proline isomerization reaction has been studied intensively, yet the precise mechanism remains to be firmly established. Although binding of CsA or FK-506 to their respective immunophilins inhibits the PPI activity, inhibition of PPI activity is irrelevant to the mechanism of immunosuppression because PPI activity is not required for T-lymphocyte activation. Within each family, the different cyclophilin and FKBP members bind to their cognate drug with varying degrees of affinity. Furthermore, not all members of each family are relevant to the immunosuppressive action of CsA or FK-506. This is because not all CyP-CsA complexes, nor all FKBP-FK-506 complexes, are equally capable of binding to CaN. Despite our understanding of how the immunophilins function during immunosuppressive therapy, it is unlikely that these proteins evolved to bind immunosuppressive molecules derived from microorganisms. Recent studies concerning the endogenous functions of the immunophilins have indicated that they bind to other proteins and that they have roles in protein folding, translocation and regulation [2].

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Wiederrecht, G., Etzkorn, F. The immunophilins. Perspectives in Drug Discovery and Design 2, 57–84 (1994). https://doi.org/10.1007/BF02171737

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Key words

  • FK-506
  • FKBP
  • Cyclophilin
  • Cyclosporin
  • Peptidyl-prolyl isomerase