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Cited by 423Heat shock proteins researchFungal and yeast genetics researchProtein Structure and Dynamics

Mutational Analysis of Hsp90 Function: Interactions with a Steroid Receptor and a Protein Kinase

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Nathan, Debra F., Lindquist, Susan·1995·Molecular and Cellular Biology
DOI 10.1128/mcb.15.7.3917PMC PMC230631
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Abstract

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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  • Mutations at interface I on Hsp90 (G333, K414, K418, K419) or Hsp70 (R171, N174, D213) cause defective Hsp90-Hsp70 interaction, growth defects, and impaired maturation of GR, v-Src and luciferase.

    “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]

    The 'Isolation of hsp82 ts mutants' section lists G313S among the Hsp90 mutations selected for temperature-sensitive growth, and the results report reduced GR and v-Src activity in the mutants. The copy does not establish that these mutations disrupt Hsp90–Hsp70 binding, or report impaired luciferase maturation; it also does not identify the cited interface-I residues by the numbering used in the claim. Pages were not provided for these passages. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • 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 [9]

    The Abstract identifies GR as a transcription factor, and the Discussion says Hsp90 is continuously required to maintain GR in a hormone-activable, transcriptionally competent state. But the section “G170D behaves like a classic ts mutant” says GR remains associated with Hsp90 only until hormone triggers dissociation. The paper therefore supports a continuing requirement before hormone activation, not dependence throughout the receptor’s entire lifetime or the same requirement for all steroid hormone receptors. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • GR is a model client whose activity continuously requires Hsp90.

    “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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Research works printed but not linked: 1

  1. [33]33. In R. I. Morimoto, A. Tissieres, and C. Georgopoulos (ed.), The biology of heat shock proteins and molecular chaperones. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.

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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
DOI
10.1128/mcb.15.7.3917
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
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
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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