Squirrel Monkey Immunophilin FKBP51 Is a Potent Inhibitor of Glucocorticoid Receptor Binding¹

Abstract

Squirrel monkeys have high circulating cortisol to compensate for expression of low-affinity glucocorticoid receptors (GRs). We have demonstrated that the FK506-binding immunophilin FKBP51 is elevated in squirrel monkey lymphocytes (SML) and, in preliminary studies, have shown that squirrel monkey FKBP51 is inhibitory to GR binding. In this report, we have demonstrated that elevated FKBP51 is the unequivocal cause of glucocorticoid resistance in SML in the following ways: 1) FK506 increased GR binding in cytosol from SML in a concentration-dependent manner, an effect reproduced by rapamycin but not cyclosporin A. The apparent K6 (6.1 nM) and rank-order of steroid displacement of [3H]dexamethasone binding in FK506-treated SML cytosol are characteristic of high-affinity GR binding. 2) cytosol from COS-7 cells expressing squirrel monkey FKBP51 inhibited GR binding in cytosol from human lymphocytes by 74%. Cytosol from COS-7 cells expressing human FKBP51 inhibited GR binding by 23%. 3) expression of squirrel monkey FKBP51 increased the median effective concentration (EC50) for dexamethasone in GR transactivation studies in COS-7 cells by approximately 17-fold, compared with the EC50 in control cells. The expression of human FKBP51 increased the EC50 for dexamethasone in COS-7 cells by less than 3-fold, compared with control. Squirrel monkey FKBP51 shares 94% overall amino acid homology with human FKBP51, with 92% and 99% homology with human FKBP51 in the peptidyl-prolyl isomerase and the tetratricopeptide repeat domains, respectively. Amino acid differences in the more variable N- or C-terminal regions or in regions which join the highly homologous functional domains may be responsible for its more potent inhibitory activity.

Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes

“…Reynolds et al (16) showed that lymphocytes from squirrel monkeys, compared with human, have 13 times higher FKBP51 protein levels and incorporate more FKBP51 into GR complexes. Studies with transfected cells and cell-free approaches have clearly shown that squirrel monkey FKBP51 reduces GR hormone-binding affinity and expression of a reporter gene (16,17). Expressing human FKBP51 to similar levels resulted in some cortisol resistance, but to only one-fifth the extent caused by monkey FKBP51.…”

“…These receptors for glucocorticoids (GR) or progesterone (PR) must be assembled through an ordered pathway involving Hsp40, Hsp70, Hsp90, and an assortment of Hsp-binding cochaperones (14). A physiological consequence of FKBP51 incorporation into GR complexes was recently observed in New World primates such as squirrel monkeys (15)(16)(17)(18). These animals are hyposensitive to cortisol because of lowered GR hormone-binding affinity, similar to some clinical patients.…”

Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume

“…There is ample evidence of genetic variation affecting GR-mediated regulation of the stress response. A promising candidate gene is FKBP5, which codes for a protein FK506 binding protein 5-51, a co-chaperone of the hsp90, and regulates the affinity of the GR for cortisol (Binder 2009;Denny et al 2000;Wochnik et al 2005). Recently, a strong stressinduced increase of FKBP5 mRNA in the central amygdala has been demonstrated (Scharf et al 2011), supporting the significance of FKBP5 regulation during central GR activation.…”

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

“…Termination of this response involves binding of glucocorticoids (i.e., cortisol) at the glucocorticoid receptor. FK506‐binding protein 51( FKBP5 ) acts as a functional negative regulator of glucocorticoid receptor sensitivity by reducing binding affinity4 and restricting nuclear translocation 5…”