Immunophilin chaperones in steroid receptor signalling

Area of Science:

• Molecular Biology
• Cellular Signaling
• Biochemistry

Background:

• Steroid receptor function is modulated by immunophilin cochaperones (CyP40, FKBP51, FKBP52) and PP5, which associate with Hsp90.
• Hsp90 is a central molecular chaperone in steroid hormone signaling and receptor assembly.
• The precise roles of these cochaperones in steroid receptor complexes are still being defined.

Purpose of the Study:

• To elucidate the function of immunophilin cochaperones in steroid receptor complexes.
• To understand how these cochaperones influence receptor activity and hormone signaling.
• To explore the mechanisms by which cochaperones modulate hormone-binding affinity and transcriptional activity.

Main Methods:

• Utilized yeast and mammalian systems for studying cochaperone function.
• Analyzed crystal structures of Hsp90 and associated cochaperones.
• Investigated FKBP51 overexpression in New World primates and FKBP52 function in a yeast model for glucocorticoid receptor.

Main Results:

• Immunophilin cochaperones interact with Hsp90, forming a scaffold for steroid receptors.
• FKBP51 overexpression in primates was linked to glucocorticoid resistance by affecting hormone-binding affinity.
• FKBP52 enhances glucocorticoid receptor transcriptional activity by increasing hormone avidity via PPIase-mediated conformational changes.

Conclusions:

• Immunophilin cochaperones play selective roles in steroid receptor function, influencing hormone-binding affinity and transcriptional activity.
• Hsp90 acts as a central scaffold for the assembly of steroid receptor-immunophilin complexes.
• Hormone binding can induce immunophilin exchange within receptor complexes, directing nuclear translocation.