Molecular Chaperone Interactions with Steroid Receptors: an Update

In the 3 yr since William Pratt and David Toft published their comprehensive review of chaperone interactions with steroid receptors (1), progress has been made on several fronts that gives a better appreciation for the range of functions that chaperones serve in mediating steroid signaling. Steroid receptors remain the best characterized examples of an ever growing assortment of cytoplasmic and nuclear proteins—diverse representatives from multiple signal transduction pathways—that rely on molecular chaperones for folding, stabilization, or functional modulation. Chaperone targets include multiple tyrosine and serine/threonine kinases (2), the arylhydrocarbon receptor (3–8), the heat shock transcription factor (9–11), common p53 mutants (Ref. 12 and references therein), nitric oxide synthase (13–15), and telomerase (16)—an impressive list of “hot topic” proteins. Often, investigators have restricted their interpretations of chaperone interactions as a simple reflection of folding insufficiency by the target protein. Supporting this view are two major facts: 1) chaperones generally function in overseeing protein folding processes and 2) it is commonly observed that the target signaling protein will fail to achieve its functional state and is more rapidly degraded by the proteolytic machinery when major chaperone interactions are disrupted. As with other targets, steroid receptors display functional instabilities when deprived of certain chaperones, and thus fit the mold of unstable protein target, but it is hoped that the reader will be convinced by recent findings that chaperone interactions with steroid receptors and, by extension, with unrelated signaling targets, serve a variety of functions that go beyond the simple explanation of folding insufficiency. ASSEMBLY OF STEROID RECEPTORCHAPERONE COMPLEXES: THE BASICS