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

Abstract

The ability to bind immunosuppressive drugs such as cyclosporin and FK506 defines the immunophilin family of proteins, and the FK506-binding proteins form the FKBP subfamily of immunophilins. Some FKBPs, notably FKBP12 (the 12-kDa FK506-binding protein), have defined roles in regulating ion channels or cell signaling, and well established structures. Other FKBPs, especially the larger ones, participate in important biological processes, but their exact roles and the structural bases for these roles are poorly defined. FKBP51 (the 51-kDa FKBP) associates with heat shock protein 90 (Hsp90) and appears in functionally mature steroid receptor complexes. In New World monkeys, FKBP51 has been implicated in cortisol resistance. We report here the x-ray structures of human FKBP51, to 2.7 Å, and squirrel monkey FKBP51, to 2.8 Å, by using multiwavelength anomalous dispersion phasing. FKBP51 is composed of three domains: two consecutive FKBP domains and a three-unit repeat of the TPR (tetratricopeptide repeat) domain. This structure of a multi-FKBP domain protein clarifies the arrangement of these domains and their possible interactions with other proteins. The two FKBP domains differ by an insertion in the second that affects the formation of the progesterone receptor complex.

Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells

“…11,27 Herein, we showed a novel role for FKBP51 as a marker of melanocyte malignancy and involvement in the protection of melanoma against Rx-induced apoptosis. FKBP51 is a large immunophilin that exerts important biological functions in the cell, among which is the regulation of the steroid hormone response as a component of the steroid hormone receptor complex 28 and the control of NF-kB activation as a cofactor of the IKKa subunit in the IKK complex. 29 Our data showed that FKBP51 has a relevant role in counteracting apoptotic processes stimulated by Rx.…”

On the role, ecology, phylogeny, and structure of dual-family immunophilins

“…As shown (Fig. 2), in all four models the three domains of the structure are clearly discernible: the FKBP domain (with five antiparallel β-strands around a central α-helix, the so-called FK fold) (Sinars et al 2003), the three-TPR linker (i.e., helix-turn-helix × 3; abbreviated as 3TPR), followed by the CYN domain. While each domain structure is largely constant as expected, it is instructive that they show various degrees of orientation relative to each other, clearly due to both rotational and torsional flexibility of the 3TPR linker (Fig.…”

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

“…K422 is located in this C-terminal tail region, which has not yet been crystallized. 4 It is likely that the modification of K422 by SUMO might modulate the conformation of this region for FKBP51-Hsp90 interaction. Interestingly, in silico analysis reveals that Hsp90 bears SUMO-interacting motifs, which can mediate non-covalent SUMO binding and cooperate in interactions between binding partners and SUMOylated proteins.…”

“…The following plasmids used in this work were previously described, as indicated: FLAG-FKBP51 and FLAG-FKBP52; 5 GSTUbc9; 47 HA-GR and the GR reporter plasmid pΔ(TAT) 4 -Luc (TAT4-luc); 18 the NF-κB reporter plasmid (κB-luc); 48 and FLAG-Hsp90 and the Gaussia luciferase reporter plasmid. 32 The pHC-RED1-C1 plasmid was obtained from Clontech (Mountain View, CA, USA).…”

“…2 The TPR domain, which is involved in protein-protein interactions, mediates its binding to Hsp90. 3,4 Through its interaction with Hsp90, FKBP51 is recruited to the GR heterocomplex to finally inhibit GR activity. 5 Therefore, FKBP51 is critical for GR in vivo function and a key mediator during stress.…”