Table 1.
Modulation of steroid hormone signalling by steroid receptor-associated immunophilins.
| TPR Immunophilin | Interaction target | Role |
|---|---|---|
| FKBP51 | GR | FKBP51 is the preferred TPR immunophilin (along with PP5) for GR-Hsp90 complexes. FKBP51 inhibits GR function by reducing receptor hormone binding affinity resulting in decreased glucocorticoid sensitivity 55–58 GR-mediated upregulation of FKBP51 results in an inhibitory feedback mechanism to further decrease glucocorticoid sensitivity.78–79 The FKBP51 FK1 domain is proposed to make direct contact with the GR ligand-binding domain to reduce hormone-binding activity.46 FKBP51 Leu119 in the corresponding proline-rich loop of the FKBP51 FK1 domain disrupts functional contact within AR, GR, PR ligand-binding domains.86 |
| FKBP51 | AR | FKBP51 overexpression increases AR transcriptional activity by promoting AR assembly with mature FKBP51-Hsp90-p23 complexes and higher levels of androgen-ligated AR.131 |
| FKBP52 | GR | FKBP52 enhances GR transcriptional activity by increasing hormone-binding affinity and nuclear transport.46,59,80 The FKBP52 FK1 domain is proposed to make direct contact with the GR ligand-binding domain to increase hormone-binding affinity 46 |
| FKBP52 | AR, PR | Mouse knockout studies have revealed a critical physiological role for FKBP52 in cellular responses controlled by AR, PR, but not ERα, MR.83–85 The proline-rich loop in the FKBP52 FK1 domain makes specific contact with the receptor ligand-binding domain to increase hormone-binding affinity and potentiation of AR, GR, PR. FKBP52 Pro119 has been identified as the critical contact proline. 86 |
| CyP40 | ERα | CyP40 is the preferred immunophilin for ERα.21,39 |
| Cpr7 | ERα, GR | Deletion of Cpr7 in yeast adversely affects ERα, GR transcriptional activity. Receptor regulation is delineated to the TPR domain.73–75 |
| CyP40 | AR | Knockdown of CyP40 or select targeting of CyP40 by CsA inhibits AR activity in LNCaP cells.72 |
| PP5 | GR | A preferred TPR immunophilin (together with FKBP51) for GR-Hsp90 complexes.47 Knockdown of PP5 enhances GR transcriptional activity without affecting hormone-binding affinity, pointing to a role for PP5 in GR nucleocytoplasmic shuttling. 48 There is evidence of PP5-dependent modulation of GR phosphorylation and transcriptional activity.87 PP5 controls the balance between lipolysis and lipogenesis by preventing GR hyperphosphorylation and inhibiting GR activity.7,89–91 |
| PP5 | MR | Ligand binding caused FKBP51 to be replaced by PP5 in MR-Hsp90 complexes.49 |
| PP5 | ERα | PP5 functions as a negative regulator of ERα transcriptional activity by inhibiting phosphorylation of specific residues in the receptor N-terminal domain. 88 |
AR, androgen receptor; CsA, cyclosporin A; CyP40, cyclophilin 40; ERα, oestrogen receptor; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PP5, protein phosphatase 5; PR, progesterone receptor; TPR, tetratricopeptide repeat