Binding of p23 and hsp90 during assembly with the progesterone receptor.
Open accessAbstract
Upon incubation in rabbit reticulocyte lysate, the unactivated progesterone receptor (PR) associates with the heat shock proteins hsp90 and hsp70, the immunophilins FKBP52, FKBP54, and CyP-40, and another protein p23. We have previously described a protein complex between p23, hsp90, and the immunophilins that forms in rabbit reticulocyte lysate in the absence of the PR. Immunodepletion of p23 from lysate prevented the binding of hsp90 and CyP-40 to the PR, suggesting that hsp90, CyP-40, and p23 bind the receptor as a complex. We have further examined the properties of this p23 complex to determine how it is involved in receptor assembly in vitro. Use was made of three chemical probes, sodium molybdate, the nonhydrolyzable ATP analog, 5'-adenylylimidodiphosphate, and the hsp90-binding agent geldanamycin. Molybdate has previously been shown to stabilize the heat-induced dissociation of hsp90 and p23 from the PR. This stabilization is not mediated through the PR, as molybdate stabilizes the heat-induced dissociation of hsp90 from p23 even in the absence of the PR. Molybdate also stabilizes both p23 and PR complexes under conditions of low ATP and magnesium concentration. The ATP analog, 5'-adenylylimidodiphosphate, which does not support the assembly of PR complexes, promotes both the assembly and stabilization of p23 complexes. Geldanamycin disrupts p23 complexes, and when PR complexes are treated with this agent, p23, CyP-40, and some hsp90 are lost from the receptor. Thus, all three of these chemical agents appear to target the p23 complex, which is thought to enter at the last step in the assembly of the PR complex. A model is presented to relate these findings to previous models and another complex between hsp90, hsp70, and p60 that appears to be an intermediate in PR assembly.
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Sodium molybdate stabilizes Hsp90's closed conformation, probably by mimicking a gamma-phosphate to stabilize the post-ATP hydrolysis transition state.
“20 mM sodium molybdate (used to stabilize the closed conformation of Hsp9011,42,43, likely by acting as a γ-phosphate analog to stabilize the post-ATP hydrolysis transition state of Hsp90 (Extended Data Fig. 2c))”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [42]
The sections “Molybdate and AMP-PNP Stabilization of p23 Complexes” and “Disruption of p23 Complexes by GA” report that sodium molybdate stabilizes Hsp90-containing complexes and discuss an ATP-like conformational change in Hsp90. They do not identify that conformation as closed or propose γ-phosphate mimicry of a post-ATP-hydrolysis transition state; the paper says the stabilizing mechanism is unknown. Page numbers were not available in our copy. (LLM, conf=0.87)
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References 20 · Cited by 233
Research works printed but not linked: 1
- Pratt WB 1992 Control of steroid receptor function and cytoplasmic-nuclear transport by heat shock proteins. BioEssays 14:841-848 Downloaded from https://academic.oup.com/mend/article/9/6/670/2715162 by guest on 18 April 2024 MOL END0 1995 678 Vol 9 No. 6 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
- Authors
- Johnson, J. L., & Toft, D. O.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Johnson, J L
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1995-06
- Volume
- 9
- Issue
- 6
- Pages
- 670-678
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2093305392
- Cited by
- 233
- References
- 20
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 2 · 2014: 8 · 2013: 8 · 2012: 5
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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 › Signaling Pathways in Disease
- Keywords
- progesterone receptor, p23, HSP90, HSP70, immunophilins, FKBP52, protein complex formation, heat shock proteins, geldanamycin, sodium molybdate, receptor activation
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Adenylyl Imidodiphosphate, Amino Acid Isomerases, Animals, Apyrase, Carrier Proteins, DNA-Binding Proteins, Edetic Acid, Heat-Shock Proteins, Molybdenum, Nucleotides, Phosphoproteins, Protein Binding, Quinones, Rabbits, Receptors, Progesterone, Reticulocytes, Benzoquinones, Molecular Chaperones, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Peptidylprolyl Isomerase, Cyclophilins, Tacrolimus Binding Proteins, Macromolecular Substances, Lactams, Macrocyclic
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