Minireview: the intersection of steroid receptors with molecular chaperones: observations and questions

Abstract

An involvement of molecular chaperones in the action and well-being of steroid receptors was recognized early in the molecular era of hormone research. However, this has continued to be a topic of much enquiry and some confusion. All steroid receptors associate with heat shock protein 90, the main character of a series of multiprotein chaperone complexes generally referred to as the "heat shock protein 90 chaperoning machine." Receptor association with chaperones occurs in an ordered, step-wise fashion and is necessary for the maintenance of unliganded receptor in a state ready to bind and respond to hormone. Chaperones additionally modulate how receptors respond to hormone and activate target genes. Although much is known about the participants in this chaperoning process and the consequences of chaperoning, many key questions remain unanswered, particularly those concerning molecular mechanisms, cellular dynamics, and the functions of an array of cochaperone proteins. Here, we point out several areas in need of investigation to encourage new ideas and participants in this burgeoning field.

Figure 1

Cyclic Assembly of Steroid Receptors with Molecular Chaperones Nascent receptor polypeptides enter the chaperone assembly cycle through an initial interaction with Hsp40 that, in turn, recruits Hsp70 and Hsp90 to the receptor complex. Multiple cochaperones participate along the way, including Hop, a TPR protein that links Hsp70 and Hsp90, p23, a cochaperone that stabilizes Hsp90 binding to receptor in functionally mature complexes, and any of several TPR proteins that dynamically compete for a common binding site on Hsp90 within the mature complex. Additional cochaperones influence receptor assembly or favor receptor degradation at the proteasome. Hormone binding disrupts the chaperone assembly cycle and promotes activation of receptor as a transcription factor. REC, Receptor.

Figure 2

Chaperone Influences on Cellular Actions of Steroid Receptors Chaperone activity varies based on the repertoire of chaperone components expressed in the cell, the relative levels of each component, and posttranslational modifications. Primarily through alterations of receptor conformation, the chaperones influence receptor hormone binding properties, receptor posttranslational modifications, subcellular localization of receptor, receptor interactions with chromatin and transcriptional cofactors, as well as receptor proteolytic half-life.