GCUNC-45 is a novel regulator for the progesterone receptor/hsp90 chaperoning pathway

The HSP90 chaperoning pathway is a multiprotein system that is required for the production or activation of many cell regulatory proteins, including the Progesterone Receptor (PR). We report here the identity of GCUNC-45 as a novel modulator of PR chaperoning by HSP90. GCUNC-45, previously implicated in the activities of myosins, can interact in vivo and in vitro with both PR-A and PR-B and with HSP90. Overexpression and knockdown experiments show GCUNC-45 to be a positive factor in promoting PR function in the cell. GCUNC-45 binds to the ATP-binding domain of HSP90 to prevent the activation of its ATPase activity by the cochaperone Aha1. This effect limits PR chaperoning by HSP90, but this can be reversed by FKBP52, a cochaperone that is thought to act later in the pathway. These findings reveal a new cochaperone binding site near the N terminus of HSP90, add insight on the role of FKBP52, and identify GCUNC-45 as a novel regulator of the PR signaling pathway.