Fig. 5: Mechanism of GR regulation by FKBP51 and FKBP52 during the GR chaperone cycle.

Schematic depicting how the FKBP co-chaperones integrate with the GR chaperone cycle and how this cycle may take place within a cellular context. Starting on the top left, GR (yellow, cartoon representation) is in dynamic equilibrium between cortisol-bound and unbound (apo) states. Hsp70 (orange) binds GR and locally unfolds GR to inhibit cortisol binding, stabilizing GR in a partially unfolded, apo state. Hsp70 transfers the partially unfolded GR to Hsp90 (light and dark blue):Hop (pink) to form the GR–loading complex¹², in which GR is stabilized in a partially unfolded, apo state. Cortisol (pink), which enters the cell through diffusion, binds to GR during the transition from the GR–loading complex to the GR–maturation complex when Hsp90 refolds the GR to a native conformation¹³. In the GR–maturation complex, the cortisol-bound, folded GR is stabilized by Hsp90 and p23 (green) and is protected from Hsp70 re-binding. Depending on the relative concentrations of the FKBPs, either FKBP51 (purple) or FKBP52 (teal) can bind the GR:Hsp90:p23 complex, competing with p23, and stabilizing the rotated position of GR. FKBP51 sequesters GR:Hsp90 in the cytosol until ATP hydrolysis on Hsp90 allows release of GR back to the chaperone cycle. In contrast, FKBP52 promotes rapid nuclear translocation of GR:Hsp90 (refs. ^22,24,25,65). Once in the nucleus, the cortisol-bound GR can dimerize, nucleate the assembly of transcriptional regulatory complexes, and regulate transcription, including activating expression of FKBP51, leading to a negative feedback loop that regulates GR activity in the cell^{27,66,67,68,69,70}.