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Mutational Analysis of Hsp90 Function: Interactions with a Steroid Receptor and a Protein Kinase
Open accessAbstract
Hsp90 is a protein chaperone whose functions are focused on a specific set of target proteins. The nature of Hsp90's interactions with these proteins is poorly understood. To provide tools for examining these interactions, we have isolated eight broadly distributed temperature-sensitive (ts) point mutations in the Hsp90 gene (HSP82) of Saccharomyces cerevisiae. The mutants fall into two distinct classes. One has a classic ts phenotype, with nearly wild-type activity at 25 degrees C and a precipitous loss of function at 34 degrees C. The remaining seven mutants, in contrast, cause a general reduction in Hsp90 function and are ts because they do not provide the high level of function required for growth at high temperatures. The effects of these mutants on two target proteins, a transcription factor (glucocorticoid receptor) and a tyrosine kinase (pp60v-src), provided several insights on Hsp90 function. First, Hsp90 is not only required to help the glucocorticoid receptor achieve a hormone-activable state, it is continuously required to maintain that state. Second, Hsp90's function in the maturation of pp60v-src involves separable roles in protein accumulation and kinase activation. Thus, Hsp90 is an integral component of both the steroid receptor and kinase signaling pathways. Finally, all eight point mutants affect the activation of both the glucocorticoid receptor and pp60v-src, indicating that Hsp90 promotes the activity of these very different target proteins through common mechanisms.
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“This explains why mutations at interface I on either Hsp90 (G333, K414, K418, K419)21–23 or Hsp70 (R171, N174, D213)24 led to defective Hsp90-Hsp70 interaction, growth defects and impaired client maturation of GR, v-Src and luciferase (Fig. 1d, e, Extended Data Fig. 4c–h; see Supplementary Table 3 for equivalent yeast residue numbering).”
From Structure of Hsp90–Hsp70–Hop–GR reveals the Hsp90 client-loading mechanism (2022) · cites this paper as [21]
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“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 [9]
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“The glucocorticoid receptor (GR) is a model client that constantly depends on Hsp90 for activity4-9.”
From Structure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism (2022) · cites this paper as [9]
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Metadata
- Authors
- Nathan, D. F., & Lindquist, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lindquist, Susan
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-07
- Volume
- 15
- Issue
- 7
- Pages
- 3917-3925
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC230631
- OpenAlex
- W2101287778
- Cited by
- 423
- References
- 56
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 8 · 2023: 7 · 2022: 7 · 2021: 12 · 2020: 14 · 2019: 14 · 2018: 9 · 2017: 8 · 2016: 11 · 2015: 5 · 2014: 14 · 2013: 11 · 2012: 15
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5f32gm014745-03)
- National Institute of General Medical Sciences (GM14745-02)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- HSP90, temperature-sensitive mutants, glucocorticoid receptor, pp60v-src, tyrosine kinase, steroid receptor signaling, kinase activation, Saccharomyces cerevisiae
- MeSH terms
- DNA Mutational Analysis, Hot Temperature, Heat-Shock Proteins, Phenotype, Protein Binding, Receptors, Glucocorticoid, Saccharomyces cerevisiae, Oncogene Protein pp60(v-src), Point Mutation, HSP90 Heat-Shock Proteins, Saccharomyces cerevisiae Proteins
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