Hsp90 is crucial to cellular signaling by its regulation of the folding, activity, and stability of a wide range of client proteins. These client protein complexes may also contain one or more co-chaperones.¹One class of Hsp90-binding co-chaperone is composed of proteins with a characteristic tetratricopeptide repeat (TPR) domain that forms an Hsp90 binding site. Among the TRP co-chaperones of Hsp90 are Hop/Sti1, protein phosphatase PP5, and members of both the FK506-and cyclosporin A-binding families of immunophilins.²FK506-binding protein 51 (FKBP51) and FKBP52 are large molecular weight immunophilins that are part of the mature glucocorticoid receptor (GR) heterocomplex.³The N-terminal domain of each protein binds FK506 and has peptidyl-prolyl isomerase (PPlase) activity that converts prolyl peptide bonds within target proteins fromcis-to trans-proline. The C-terminal domains contain the TRP repeats involved in protein-protein interactions with Hsp40.⁴Although FKBP52 and FKBP51 share ~75% sequence similarity, they affect hormone binding by the glucocorticoid receptor in opposing manners and have different Hsp90-binding characteristics.^3,5Also, whereas FKBP51 typically has a role with the progesterone receptor, FKBP52 has been found to be linked to the progesterone, androgen, and glucocorticoid receptors.⁵

1.Cheung-Flynn, J., Roberts, P.J., Riggs, D.L., et al.C-terminal sequences outside the tetratricopeptide repeat domain of FKBP51 and FKBP52 cause differential binding to Hsp90The Journal of Biological Chemisty278(19)17388-17394(2003) 2.Davies, T.H., Ning, Y.M., and SÁnchez, E.R.A new first step in activation of steroid receptors. Hormone-induced switching of FKBP51 and FKBP52 immunophilinsThe Journal of Biological Chemisty277(7)4597-4600(2002) 3.Wu, B., Li, P., Liu, Y., et al.3D structure of human FK506-binding protein 52: Implications for the assembly of the glucocorticoid receptor/Hsp90/immunophilin hetrocomplexThe Journal of Biological Chemisty101(22)8348-8353(2004) 4.Denny, W.B., Prapapanich, V., Smith, D.F., et al.Structure-function analysis of squirrel monkey FK506-binding protein 51, a potent inhibitor of glucocorticoid receptor activityEndocrinology146(7)3194-3201(2005) 5.Cox, M.B., Riggs, D.L., Hessling, M., et al.FK506-binding protein 52 phosphorylation: A potential mechanism for regulating steroid hormone receptor activityMol. Endocrinol.21(12)2956-2967(2007)