Functional Protein Interactions in Steroid Receptor-Chaperone Complexes

Abstract

Heat shock protein 90 (Hsp90) is unique in that it chaperones a select group of client proteins and assists their folding in preparation for key regulatory roles in cellular signalling. Steroid receptors are among the most extensively studied Hsp90 chaperone substrates and belong to the large nuclear receptor superfamily of hormone-activated transcription factors that respond to hormonal cues through conformational changes induced by hormone binding within the ligand-binding domain (LBD). In an ATPdependent assembly process, high affinity hormone binding is achieved through the direct interaction of the steroid receptor LBD with Hsp90 and specific Hsp90-associated chaperones. After synthesis, steroid receptors enter the Hsp90 chaperoning pathway by initial assembly with Hsp40, followed by incorporation of Hsp70 and Hip. The binding of Hop and Hsp90 then generates an intermediate receptor complex which is further modified by the release of Hsp70 and Hop, allowing a transition of the receptor to hormone-binding competency. Recruitment of p23 leads to formation of mature receptor complexes capable of binding hormone with high affinity and characterized by the additional presence of one of the immunophilin cochaperones, FKBP51, FKBP52, CyP40 and PP5. This dynamic assembly of receptors to a hormone-activatable state, together with a selective functionality of receptors associated with specific Hsp90-immunophilin complexes provides mechanisms through which Hsp90 and the immunophilin cochaperones may regulate hormone-induced signalling events. This may occur directly by enhancing hormone binding as has been observed for AR, GR and PR associated with Hsp90-FKBP52 complexes or indirectly by facilitating nuclear import of receptor as seen