Structural and biochemical insights into FKBP51 as a Hsp90 co-chaperone

Abstract

The FK506-binding protein 51 (FKBP51) is a high-molecular-weight immunophilin that emerged as an important drug target for stress-related disorders, chronic pain, and obesity. It has been implicated in a plethora of molecular pathways but remains best characterized as a co-chaperone of Hsp90 in the steroid hormone receptor (SHR) maturation cycle. However, the mechanistic and structural basis for the regulation of SHRs by FKBP51 and the usually antagonistic function compared with its closest homolog FKBP52 remains enigmatic. Here we review recent structural and biochemical studies of FKBPs as regulators in the Hsp90 machinery. These advances provide important insights into the roles of FKBP51 and FKBP52 in SHR regulation.

Keywords: SAFit2; fkbp51; fkbp52.

Figure 1

Structure of full‐length FK506‐binding protein 51 (FKBP51). The FK1 domain (salmon), followed by the FK2 domain (blue), the tetratricopeptide repeat (TPR) domain (green) in complex with the MEEVD‐containing peptide derived from the Hsp90 C terminus (magenta spheres) and the C‐terminal extended helix 7 (cyan) (PDB‐ID: 5NJX). The FK1 domain (enlarged) with FK506 (yellow) bound is superimposed (PDB‐ID: 3O5R) with the residues important for Peptidyl‐Prolyl‐Isomerase (PPIase) activity or binding of selective ligands highlighted in red.

Figure 2

The cellular role of FK506‐binding protein 51 (FKBP51). FKBP51 and FKBP52 act as Hsp90‐dependent regulators of steroid hormone receptors. Repression by FKBP51 is represent by a red line, facilitation by a green line. Dotted lines represent interactions that are less well characterized. The competition of FKBP51 and FKBP52 is represented by a black arrow. AR, androgen receptor; ER, estrogen receptor; GR, glucocorticoid receptor; PR, progesterone receptor; SHRE, steroid hormone receptor response element.

Figure 3

Structure of the Hsp90/FK506‐binding protein 51 (FKBP51)/p23 complex (PDB‐ID: 7L7I). (A) The Hsp90 dimer (cyan and blue) in the closed conformation, with p23 (green) positioned on the opposite side of FKBP51 (light pink). (B) Detailed view on the interaction of the C‐terminal helix of FKBP51 and the C‐terminal domain of Hsp90. For clarity, the FK1 and FK2 domain of FKBP51, as well as the N‐terminal domain and middle domain of Hsp90 of the structure were omitted. The MEEVD peptide from Hsp90 is shown as spheres (magenta). (C) Structure of the Hsp90/p23/LBD^GR complex (PDB‐ID: 7L7I). (D) Overlay of the Hsp90/FKBP51/p23 structure (PDB‐ID: 7L7I) with the Hsp90/p23/LBD^GR (PDB‐ID: 7KRJ). The FK1 domain collides with the LBD^GR (magenta). p23 (green, from 7KRJ) is shown on the same side as FKBP51.