A specialized Hsp90 co-chaperone network regulates steroid hormone receptor response to ligand

Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client pro-teins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.

Automated summary

The chaperone machinery of heat shock protein-90 (Hsp90) is crucial for the stability and activity of its client proteins. Recent findings suggest that the co-chaperones FNIP1/2 and Tsc1 have an impact on Hsp90's client activity. They increase the affinity of steroid hormone receptors to their ligands, providing a model for the activation of these receptors.