Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones*

Pratt, William B.; Toft, David O.

doi:10.1210/edrv.18.3.0303

Cited by 1,791Heat shock proteins researchEstrogen and related hormone effectsReceptor Mechanisms and Signaling

Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones*

Pratt, William B., Toft, David O.·1997·Endocrine Reviews

DOI 10.1210/edrv.18.3.0303

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Abstract

We have provided a historical perspective on a body of steroid receptor research dealing with the structure and physiological significance of the untransformed 9S receptor that has often confused both novice and expert investigators. The frequent controversies and equivocations of earlier studies were due to the fact that the native, hormone-free state of these receptors is a large multiprotein complex that resisted description for many years because of its unstable and dynamic nature. The untransformed 9S state of the steroid and dioxin receptors has provided a unique system for studying the function of the ubiquitous, abundant, and conserved heat shock protein, hsp90. The hormonal control of receptor association with hsp90 provided a method of manipulating the receptor heterocomplex in a manner that was physiologically meaningful. For several steroid receptors, binding to hsp90 was required for the receptor to be in a native hormone-binding state, and for all of the receptors, hormone binding promoted dissociation of the receptor from hsp90 and conversion of the receptor to the DNA-binding state. Although the complexes between tyrosine kinases and hsp90 were discovered earlier, the hormonal regulation or steroid receptor association with hsp90 permitted much more rapid and facile study of hsp90 function. The observations that hsp90 binds to the receptors through their HBDs and that these domains can be fused to structurally different proteins bringing their function under hormonal control provided a powerful linkage between the hormonal regulation of receptor binding to hsp90 and the initial step in steroid hormone action. Because the 9S receptor hsp90 heterocomplexes could be physically stabilized by molybdate, their protein composition could be readily studied, and it became clear that these complexes are multiprotein structures containing a number of unique proteins, such as FKBP51, FKBP52, CyP-40, and p23, that were discovered because of their presence in these structures. Further analysis showed that hsp90 itself exists in a variety of native multiprotein heterocomplexes independent of steroid receptors and other 'substrate' proteins. Cell-free systems can now be used to study the formation of receptor heterocomplexes. As we outlined in the scheme of Fig. 1, the multicomponent receptor-hsp90 heterocomplex assembly system is being reconstituted, and the importance of individual proteins, such as hsp70, p60, and p23, in the assembly process is becoming recognized. It should be noted that our understanding of the mechanism and purpose of steroid receptor heterocomplex assembly is still at an early stage. We can now speculate on the roles of receptor-associated proteins in receptor action, both as individuals and as a group, but their actual functions are still vague or unknown. We can make realistic models about the chaperoning and trafficking of steroid receptors, but we don't yet know how these processes occur, we don't know where chaperoning occurs in the cell (e.g. Is it limited to the cytoplasm? Is it a diffuse process or does chaperoning occur in association with structural elements?), and, with the exception of the requirement for hormone binding, we don't know the extent to which the hsp90-based chaperone system impacts on steroid hormone action. It is not yet clear how far the discovery of this hsp90 heterocomplex assembly system will be extended to the development of a general understanding of protein processing in the cell. Because this assembly system is apparently present in all eukaryotic cells, it probably performs an essential function for many proteins. The bacterial homolog of hsp90 is not an essential protein, but hsp90 is essential in eukaryotes, and recent studies indicate that the development of the cell nucleus from prokaryotic progenitors was accompanied by the duplication of genes for hsp90 and hsp70 (698). (ABSTRACT TRUNCATED)

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Steroid hormone receptors including the glucocorticoid receptor are hormone-regulated transcription factors that depend on Hsp90 for function throughout their lifetimes.
“SHRs, including the glucocorticoid receptor (GR), are hormone-regulated transcription factors that depend on Hsp90 for function throughout their lifetimes5–10.”
From Cryo-EM reveals how Hsp90 and FKBP immunophilins co-regulate the glucocorticoid receptor (2023) · cites this paper as [6]
FKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus.
“FKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus (29,30).”
From Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation (2016) · cites this paper as [29]
Hsp90 is an ATP-utilizing chaperone that interacts transiently with LBDs to stabilize a conformation appropriate for ligand binding.
“The central player in this reaction is Hsp90, an ATP-utilizing chaperone that interacts transiently with LBDs to stabilize a conformation that is appropriate for ligand binding (24).”
From FKBP51 Promotes Assembly of the Hsp90 Chaperone Complex and Regulates Androgen Receptor Signaling in Prostate Cancer Cells (2010) · cites this paper as [24]

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BackgroundMethodInfluential
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Background
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“B, C4-2 cells were transfected with expression vectors for GFP-tagged NTD, AR(1-293), and AR(294-556), along”
BackgroundMethod
Lymphocyte glucocorticoid receptor expression level and hormone-binding properties differ between war trauma-exposed men with and without PTSD
Matić, G., Milutinović, D. V., Nestorov, J., Elaković, I., Jovanović, S. M., Perišić, T., Dunđerski, J., Damjanović, S., Knežević, G., Špirić, Ž., et al. (2013) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2013.01.005 · Cited by 43 · see citing works

Authors: Pratt, W. B., & Toft, D. O.
Affiliations: University of Michigan (US)
Mayo Clinic (US)
Venue: Endocrine Reviews
Publisher: The Endocrine Society
Published: 1997-06-01
Volume: 18
Issue: 3
Pages: 306-360
ISSN: 0163-769X (ISSN-L)
1945-7189
DOI: 10.1210/edrv.18.3.0303
OpenAlex: W2010142538
Cited by: 1,791
References: 19
Citations by year: 2026: 4 · 2025: 13 · 2024: 19 · 2023: 26 · 2022: 34 · 2021: 37 · 2020: 23 · 2019: 53 · 2018: 54 · 2017: 49 · 2016: 58 · 2015: 65 · 2014: 51 · 2013: 74 · 2012: 53
FWCI: 5.83
Type: journal article
Language: en
Open access: closed
Locations: Endocrine Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA028010, CA 28010)
National Institute of Diabetes and Digestive and Kidney Diseases (DK31573)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 09140)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: steroid hormone receptors, HSP90, heat shock proteins, immunophilins, hormone-binding domain, FKBP51, FKBP52, p23, HSP70, P60, aryl hydrocarbon receptor, steroid hormone action, DNA binding
MeSH terms: Animals, Carrier Proteins, Heat-Shock Proteins, Humans, Immunosuppressive Agents, Molybdenum, Receptors, Steroid, Molecular Chaperones, HSP90 Heat-Shock Proteins

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Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones*

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