The Many Faces of FKBP51

Abstract

The FK506-binding protein 51 (FKBP51) has emerged as a key regulator of endocrine stress responses in mammals and as a potential therapeutic target for stress-related disorders (depression, post-traumatic stress disorder), metabolic disorders (obesity and diabetes) and chronic pain. Recently, FKBP51 has been implicated in several cellular pathways and numerous interacting protein partners have been reported. However, no consensus on the underlying molecular mechanisms has yet emerged. Here, we review the protein interaction partners reported for FKBP51, the proposed pathways involved, their relevance to FKBP51's physiological function(s), the interplay with other FKBPs, and implications for the development of FKBP51-directed drugs.

Keywords: FK506; FKBP51; GR; Hsp90; NF-κB; SAFit; glucocorticoids.

Figure 1

Full length FK506-binding protein 51 (FKBP51, PDB-ID: 1KT0) bound to the MEEDV motif derived from the heat shock protein 90 (Hsp90) C-terminus (PDB-ID: 5NJX). FK506 bound to the FK1 domain is superimposed from PDB-ID: 3O5R. TPR: tetratricopeptide repeat.

Figure 2

Structure of the FKBP51 FK1 domain. Conserved binding pocket amino acids are depicted in yellow (PDB-ID: 3O5E).

Figure 3

FK1 domain bound to the selective ligand iFit4 (PDB-ID: 4TW7). The Phe67-in state is superimposed from PDB-ID: 5OBK.

Figure 4

Overview of known FKBP51 interactors within their respective field of discovery. Stronger arrows indicate a larger data set of this specific interaction. MR: mineralocorticoid receptor; CDK: cyclin-dependent kinase; ER: estrogen receptor NFκB: nuclear factor binding near the κ light-chain in B-cells; USP: ubiquitin-specific protease

Figure 5

Chemical structures of important FKBP51 ligands.