Regulation of steroid hormone receptor function by the 52-kDa FK506-binding protein (FKBP52)

Abstract

The large FK506-binding protein FKBP52 has been characterized as an important positive regulator of androgen, glucocorticoid and progesterone receptor signaling pathways. FKBP52 associates with receptor-Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. Data from biochemical and cellular studies have been corroborated in whole animal models as fkbp52-deficient male and female mice display characteristics of androgen, glucocorticoid and/or progesterone insensitivity. FKBP52 receptor specificity and the specific phenotypes displayed by the fkbp52-deficient mice have firmly established FKBP52 as a promising target for the treatment of a variety of hormone-dependent diseases. Recent studies demonstrated that the FKBP52 FK1 domain and the proline-rich loop within this domain are functionally important for FKBP52 regulation of receptor function. Based on these data, efforts are currently underway to target the FKBP52 FK1 domain and the proline-rich loop with small molecule inhibitors.

Figure 1. Three-Dimensional Structure for FKBP52

A composite of two partial structures for human FKBP52 (protein databank numbers 1Q1C and 1P5Q). The left panel illustrates the FKBP52 structure in ribbon format and the right panel in molecular surface format. The individual domains as well as regions of functional importance are individually colored. The TPR domain (red) allows association with Hsp90-receptor complexes through interaction with the Hsp90 EEVD motif. The FK1 domain (blue) contains the PPIase active site as well as the proline-rich loop (orange), which is proposed to serve as an interaction surface. FK1 is linked to the FK2 domain (green) by way of the FK Linker (yellow). FK2, although similar to FK1, lacks PPIase activity. The FK Linker contains a casein kinase 2 phosphorylation site that, when phosphorylated, abrogates FKBP52 function. The two partial structures were overlayed and the figure was created using UCSF Chimera version 1.5.

Figure 2. FKBP52 Interactions and Targeting Strategies

Interactions: Known (solid arrow) and predicted (dashed arrow) interactions between FKBP52, Hsp90 and the receptor are shown. FKBP52 is known to interact with the C-terminal EEVD on Hsp90 and Hsp90 interacts with the receptor ligand binding domain. Based on the available evidence it is hypothesized that Hsp90 brings the FKBP52 FK1 domain, the proline-rich loop in particular, in close proximity to the receptor LBD where FKBP52 at least contacts the receptor leading to regulation of receptor hormone binding and subcellular localization. Targeting the interactions: Several drugs and drug candidates are available for disrupting receptor-Hsp90 complexes. The Hsp90 inhibitor geldanamycin and derivatives bind to the N-terminal nucleotide-binding site, which disrupts complex formation and leads to receptor degradation. However, this class of compounds lacks Hsp90 client protein specificity and has been ineffective in prostate cancer. The immunosuppressive ligand FK506 binds the FKBP52 PPIase pocket and is known to disrupt FKBP52 regulation of receptor. However, this drug lacks FKBP protein specificity and is highly immunosuppressive. If the FK1 domain and the proline-rich loop do serve as an interaction surface, then targeting those interactions is likely to be a viable option.