FKBP51 and FKBP52 in signaling and disease

Abstract

FKBP51 and FKBP52 are diverse regulators of steroid hormone receptor signaling, including receptor maturation, hormone binding and nuclear translocation. Although structurally similar, they are functionally divergent, which is largely attributed to differences in the FK1 domain and the proline-rich loop. FKBP51 and FKBP52 have emerged as likely contributors to a variety of hormone-dependent diseases, including stress-related diseases, immune function, reproductive functions and a variety of cancers. In addition, recent studies have implicated FKBP51 and FKBP52 in Alzheimer's disease and other protein aggregation disorders. This review summarizes our current understanding of FKBP51 and FKBP52 interactions within the receptor-chaperone complex, their contributions to health and disease, and their potential as therapeutic targets for the treatment of these diseases.

Figure 1

FKBP51 and FKBP52 X-ray crystallographic structures. The three-dimensional structure of human FKBP51 (protein databank number 1KT0) and a composite of two partial structures for human FKBP52 (protein databank numbers 1Q1C and 1P5Q) are shown in ribbon format colored based on secondary structure. The important functional domains and regions are illustrated. The C-terminal TPR domain mediates binding to Hsp90. The FKBP12-like domains 1 and 2 are also shown. FK2 is similar to FK1 but lacks PPIase activity and does not bind the immunosuppressive ligand FK506. The FK1 domain both contains a functional PPIase active site and binds FK506. Although the PPIase activity is not required for receptor regulation, the FK1 domain is critical for FKBP function. In particular the proline-rich loop overhanging the PPIase pocket is critical for receptor regulation, is largely responsible for the divergent functions of FKBP51 and FKBP52, and may serve as a functionally important interaction surface. The figure was created, including overlaying the two partial FKBP52 structures, using UCSF Chimera version 1.5.

Figure 2

Model for FKBP regulation of receptor maturation and hormone binding. The FK1 domain, the proline-rich loop in particular, is responsible for the divergent functions of the FKBPs and likely serves as an interaction surface. The difference in the shape of the FKBP FK1 domains shown here illustrates the structural differences in the proline-rich loop between these two proteins. The current model holds that the association of the FKBPs with the closed state of the Hsp90 dimer, which is stabilized by the p23 cochaperone, brings the FK1 domain into contact with the receptor LBD to directly influence hormone binding affinity. As a result of the differences in the FK1 domain, hormone binding is repressed in the presence of FKBP51 and potentiated in the presence of FKBP52.

Figure 3

Models for steroid hormone receptor translocation. According to the classic model (dashed lines) the chaperone complex dissociates in the cytoplasm from the steroid receptor (SR) upon hormone (H) binding. This transformed receptor passes through the nuclear pore complex (NPC) to reach its nuclear sites of action. The novel model is depicted with continuous lines. Upon steroid binding, the SR heterocomplex exchanges FKBP51 (brown crescent) for FKBP52 (dashed crescent), which is able to interact with dynein (black). The chaperone complex serves as a traction chain for the receptor whose retrotransport occurs on cytoskeletal tracts. The nuclear localization signal (NL1; pink) protrudes upon steroid binding and the whole SR-chaperone complex translocates through the NPC. The heterocomplex interacts with structural proteins of the pore, which are also chaperoned. Receptor transformation is nucleoplasmic and facilitates the binding of the steroid-activated receptor with promoter sites.

Figure 4

FKBP51 is linked to the HPA axis. Upon perception of stress, CRH is released from the hypothlamus, which promotes synthesis and release of ACTH from the pituitary. ACTH in turn increases release of cortisol from the adrenal glands. The inhibitory action of cortisol-activated GR on CRH and ACTH terminates the hormonal stress response and keeps the HPA axis in balance. FKBP51 expression is increased by GR, and acts back on GR in an inhibitory manner. This ultrashort feedback loop provides a mechanism by which FKBP51 regulates HPA axis activity, affects the impact of cortisol in target tissues, and links stress to its other molecular and physiological functions.