A Specific Regulatory Role for SGT alpha in the Maturation and Activation of Steroid Hormone Receptors

Steroid hormone receptors (SHRs) are ligand-dependent transcription factors which, upon binding hormone, translocate to the nucleus and regulate the transcription of specific genes responsible for growth, development, and homeostasis of higher ordered eukaryotes gene transcription. The Hsp90-Hsp70 chaperone machinery plays a crucial role for the SHRs to achieve the hormone binding conformation. Although Hsp90 and Hsp70 are key players in this process, multiple proteins associate with the receptor-chaperone complex for maturation of the SHRs. Human small glutamine rich TPR (tetratricopeptide repeat) containing protein α (SGTα) is a newly identified protein that has been demonstrated to associate with Hsp90 and Hsp70 complexes and is a key participant in the androgen receptor (AR) signaling pathway which is responsible for prostate cancer.  Preliminary studies in the yeast reporter system demonstrate that SGTa expression can completely abrogate the regulation of receptor function by the cochaperone FKBP52. Although the logical explanation for this functional inhibition is a direct competition for binding the Hsp90 EEVD motif, we have been unable to demonstrate a direct interaction between SGTa and Hsp90. Therefore, we hypothesize that SGTα acts as a non-competitive inhibitor of FKBP52 function by binding to intermediate receptor chaperone complexes preventing the receptor from reaching the native folded state on which FKBP52 acts. Thus, future studies will be aimed at determining what factor(s) SGTa interacts with in the Hsp90 chaperoning pathway, which will ultimately lead to a better understanding of the role SGTa plays in SHR folding and function.