Regulation of the glucocorticoid response to stress‐related disorders by the Hsp90‐binding immunophilin FKBP51

Abstract

J. Neurochem. (2012) 122, 4–18. Abstract Immunophilin is the collective name given to a family of proteins that bind immunosuppressive drugs: Some immunophilins are Hsp90‐binding cochaperones that affect steroid receptor function. Mood and anxiety disorders are stress‐related diseases characterized by an impaired function of the mineralocorticoid and glucocorticoid receptors, two of the major regulatory elements of the hypothalamus‐pituitary‐adrenocortical axis. Genetic variations of the FK506‐binding protein of 51‐kDa, FKBP51, one of the immunophilins bound to those steroid receptor complexes, were associated with the effectiveness of treatments against depression and with a major risk‐factor for the development of post‐traumatic stress disorders. Interestingly, immunophilins show polymorphisms and some polymorphic isoforms of FKBP51 correlate with a greater impairment of steroid receptor functions. In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response.

Plant immunophilins: a review of their structure-function relationship

“…The major contribution to this significant difference is coming from the redox active C-terminal loop [90]. The catalytic domains are significantly shifted and twisted compared with the oxidized structure and this results in differences of up to 10 Å. Superimposition of only the catalytic domains of the reduced structure and the corresponding parts of the oxidized structure gives an RMSD of 1.48 Å for 17 Cα atoms (residues [100][101][102][103][104][105][106][107][108][109][110][111][112][113][114][115][116]. Reduction of the disulfide bond leads to an increase in the distance between the sulfur atoms of the two cysteines: the observed S-S distance in AtFKBP13-S2 Cys5-Cys17 and Cys106-Cys111 are 2.04 ± 0.01 and 2.01 ± 0.01 Å, respectively as expected for a disulfide bond, whereas the corresponding distance is 5.18 Å and 2.81 Å for AtFKBP13-(SH)2 [90].…”

“…Similarly, AtFKBP65 is a heat stress protein but fkbp65 mutant plants are resistant to heat stress and small heat shock proteins are highly expressed, contrary to what is observed in fkbp62 mutants, indicating antagonistic functions [36]. Equally, the mammalian FKBP51/FKBP52 orthologs of AtFKBP62/AtFKBP65 have also been shown to have antagonist functions in steroid receptor-mediated signaling [112,113]. On a similar note, transgenic wheat overexpressing TaFKBP73 and TaFKBP77 revealed different morphological abnormalities, indicating different functional attributes for the two isoforms in plant development [114].…”

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

“…Presumably acting via the glucocorticoid receptor, single nucleotide polymorphisms in the fkbp5 gene exhibit a strong correlation with recurrence of depressive episodes, the rate of response to antidepressant therapies, and in psychological stress disorders (9,10). As a necessary chaperone for the Akt-specific phosphatase PHLPP (11,12), FKBP51 also provides indirect feedback regulation by inhibiting glucocorticoid receptor phosphorylation via the Aktp38 kinase pathway (13,14).…”

Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships

“…As an example, members of each of the three families (Cyp40, FKBP-51, and Pin1) are able to control activation of the glucocorticoid receptor following ligand binding [46][47][48][49]. Deregulation of PPIases contributes to diseases in which protein misfolding plays a major pathogenic role, including neurodegenerative disorders and cancer.…”