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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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MethodHeat-shock protein 90, a chaperone for folding and regulation
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ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo
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“A variety of temperature-sensitive mutants of yeast Hsp90 have been identified (Nathan and Lindquist, 1995), some of which correspond to missense mutations within the N-terminal domain of the protein.”
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“Hsp90 is specifically involved in the folding and conformational regulation of a number of medically relevant signal transduction molecules, including the nuclear receptors for steroid hormones and several protooncogenic kinases (Smith, 1993; Nathan and Lindquist, 1995; Frydman and Höhfeld, 1997; Nathan et al., 1997;…”
Molecular chaperones and protein folding in plants
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“Temperature-sensitive mutants of yeast Hsp90 showed that disruption of the Hsp90 system is not toxic to the cell but induces a growth arrest until permissive temperatures allowed the Hsp90 mutants to gain back their function (Kimura et al., 1994; Nathan and Lindquist, 1995).”
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Lanneau, D., Brunet, M., Frisan, E., Solary, É., Fontenay, M., & Garrido, C. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00273.x · Cited by 518
“HSP90 associates with a number of signalling proteins including ligand-dependent transcription factors, such as steroid receptor [13], ligand-independent transcription factors, such as MyoD [14], tyrosine kinases, such as v-Src [15], and serine/threonine kinases, such as Raf-1 [16].”
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“A P F D L F E S K K K K N N-340) generating an copy number suppressor of an Hsp90 mutant allele, Glu381Lys (Nathan and Lindquist, 1995).”
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Tesnière, A., Panaretakis, T., Kepp, O., Apétoh, L., Ghiringhelli, F., Zitvogel, L., & Kroemer, G. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402269 · Cited by 509
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Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4
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Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)‐domain co‐chaperones
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“Two temperature-sensitive mutations of yeast Hsp90 (Thr22Ile, Thr101Ile) (Nathan and Lindquist, 1995) lie in this putative ‘interaction patch’, and both of these mutants show synthetic effects in the presence of Sti1 overexpression.”
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An Acetylation Site in the Middle Domain of Hsp90 Regulates Chaperone Function
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“This has been used as a phenotypic readout of the ability of various Hsp90 mutants to chaperone p60v-Src in yeast (Nathan and Lindquist, 1995; Xu and Lindquist, 1993).”
BackgroundMethodInfluentialThe hsp90-related Protein TRAP1 Is a Mitochondrial Protein with Distinct Functional Properties
Felts, S. J., Owen, B. A. L., Nguyen, P., Trepel, J. B., Donner, D. B., & Toft, D. O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.5.3305 · Cited by 380
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Self-citationHeat shock proteins, cellular chaperones that modulate mitochondrial cell death pathways
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“cerevisiae have provided some of the best evidence for the physiological roles of Hsc82/Hsp90 (Picard et al., 1990a; Bohen and Yamamoto, 1993; Nathan and Lindquist, 1995), Ydj1/ Hsp40 (Caplan et al.”
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“The structure elegantly explained the effects of a number of temperature-sensitive mutants which had been shown to have increased or decreased ATPase activity [41, 97].”
BackgroundExperimental illumination of a fitness landscape
Hietpas, R. T., Jensen, J. D., & Bolon, D. N. A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016024108 · Cited by 336
“cerevisiae cells (34) engineered with a temperature-sensitive chromosomal copy of Hsp90.”
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Sequist, L. V. D., Gettinger, S. N., Senzer, N. N., Martins, R. G., Janne, P. A., Lilenbaum, R., Gray, J. E., Iafrate, A. J., Katayama, R., Hafeez, N., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.30.8338 · Cited by 331
Conformational dynamics of the molecular chaperone Hsp90
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Aneuploidy causes proteotoxic stress in yeastPreprint
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“Compromising Hsp90 activity suppresses v-src folding and activity and, consequently, this lethality (Fig. 6B; Nathan and Lindquist 1995; Nathan et al. 1997).”
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“Initial mutational studies suggested the MD of Hsp90 as the client-binding site (Bohen and Yamamoto 1993; Nathan and Lindquist 1995; Genest et al. 2013).”
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“Yeast genetic studies by Nathan and Lindquist (18) have shown that both GR and v-src expressed in yeast cells repeatedly traverse an hsp90-mediated pathway that is required for their function.”
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“Analysis of point mutations in the hsp90 gene revealed that HSP90 function in the maturation of v-Src involves separable roles in protein accumulation and kinase activation (Nathan & Lindquist 1995).”
BackgroundFolding of the Glucocorticoid Receptor by the Heat Shock Protein (hsp) 90-based Chaperone Machinery
Dittmar, K. D., Demady, D. R., Stancato, L. F., Krishna, P., & Pratt, W. B. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21213 · Cited by 265
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“These proteins can be considered as independent test substrates, as the firefly luciferase (FFL) is a monomeric protein unrelated in sequence or structure to the heterodimeric bacterial protein (LuxAB) (Nathan and Lindquist, 1995).”
BackgroundFolding and Quality Control of the VHL Tumor Suppressor Proceed through Distinct Chaperone Pathways
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“The pESC plasmid expressing u celongin B and elongin C is described elsewhere (Melville et al., 2003). e wThe yeast strains used in this study are as follows: wt CIM3 (YPG499; MATa ura3-52 leu2-D1 his3-D200 trp1-D63 lys2-801 m 1ade2-101) and cim3-1 (CMY762; ura3-52 leu2-D1 his3-D200 cim3-1) (Ghislain et al., 1993); MH…”
Chaperoning of Glucocorticoid Receptors
Pratt, W. B., Morishima, Y., Murphy, M. N., & Harrell, M. (2005) · Springer eBooks · doi:10.1007/3-540-29717-0_5 · Cited by 247
Two chaperone sites in Hsp90 differing in substrate specificity and ATP dependence
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“The glucocorticoid and progesterone receptors and, to a lesser extent, the oestrogen receptor, have been shown to require Hsp90 in order to assemble and maintain a high-af®nity, ligand-binding state.(7,8,15) The interaction between Hsp90 and the glucocorticoid receptor has been shown to localise to the ligand-binding…”
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Polypeptide release by Hsp90 involves ATP hydrolysis and is enhanced by the co‐chaperone p23
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A Cyclophilin Function in Hsp90-Dependent Signal Transduction
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Self-citationHsp90 Regulates Androgen Receptor Hormone Binding Affinity in Vivo
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In Vivo Analysis of the Hsp90 Cochaperone Sti1 (p60)
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Self-citationStructure of Hsp90–Hsp70–Hop–GR reveals the Hsp90 client-loading mechanism
Wang, R. Y.-R., Noddings, C. M., Kirschke, E., Myasnikov, A. G., Johnson, J. L., & Agard, D. A. (2022) · Nature · doi:10.1038/s41586-021-04252-1 · Cited by 220
Heat stress proteins and transcription factors
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Coordinated ATP Hydrolysis by the Hsp90 Dimer
Richter, K., Muschler, P., Hainzl, O., & Büchner, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103832200 · Cited by 207
Cdc37 is a molecular chaperone with specific functions in signal transduction.Preprint
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Self-citationHSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes
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Direct Association with Thioredoxin Allows Redox Regulation of Glucocorticoid Receptor Function
Makino, Y., Yoshikawa, N., Okamoto, K., Hirota, K., Yodoi, J., Makino, I., & Tanaka, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.5.3182 · Cited by 204
Vaughan, C. K., Mollapour, M., Smith, J. R., Truman, A. W., Hu, B., Good, V. M., Panaretou, B., Neckers, L., Clarke, P. A., Workman, P., et al. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.07.021 · Cited by 202
“For agar growth GA sensitivity assays, overnight DO cultures (without methionine) were diluted to an optical density of 600 nm of 0.5, and z5 ml aliquots of a 10-fold dilution series were spotted onto DO-2% agar (without methionine) plates supplemented with the indicated level of GA. Growth was monitored over 3–5 days…”
BackgroundMethodInfluentialHarris, S. F., Shiau, A. K., & Agard, D. A. (2004) · Structure · doi:10.1016/j.str.2004.03.020 · Cited by 200
Structure, function, and mechanism of the Hsp90 molecular chaperone
Pearl, L. H., & Prodromou, C. (2001) · Advances in protein chemistry · doi:10.1016/s0065-3233(01)59005-1 · Cited by 199
Stancato, L. F., Silverstein, A. M., Owens-Grillo, J. K., Chow, Y., Jove, R., & Pratt, W. B. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.7.4013 · Cited by 201
Swe1Wee1-Dependent Tyrosine Phosphorylation of Hsp90 Regulates Distinct Facets of Chaperone Function
Mollapour, M., Tsutsumi, S., Donnelly, A. C., Beebe, K., Tokita, M. J., Lee, M.-J., Lee, S., Morra, G., Bourboulia, D., Scroggins, B. T., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.005 · Cited by 196
“The oncogenic tyrosine kinase v-Src is a well-known Hsp90 client protein (Nathan and Lindquist, 1995).”
Taxis, C., Hitt, R., Park, S.-H., Deák, P., Kostova, Z., & Wolf, D. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301080200 · Cited by 192
Hsp90 Mediates Membrane Deformation and Exosome Release
Lauwers, E., Wang, Y.-C., Gallardo, R. U., van der Kant, R., Michiels, E., Swerts, J., Baatsen, P., Zaiter, S. S., McAlpine, S. R., Gounko, N. V., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.016 · Cited by 188
Xu, Y., Singer, M. A., & Lindquist, S. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.1.109 · Cited by 184
Self-citationO'Keeffe, B. A., Fong, Y. W., Chen, D., Zhou, S., & Zhou, Q. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.1.279 · Cited by 177
Steroid Receptor Interactions with Heat Shock Protein and Immunophilin Chaperones*
Pratt, W. B., & Toft, D. O. (1997) · Endocrine Reviews · doi:10.1210/edrv.18.3.0303 · Cited by 1,791
“For example, Nathan and Lindquist (495) showed that point mutations affecting hsp90 function with the GR in yeast also affect v-Src activity.”
BackgroundThe ‘active life’ of Hsp90 complexes
Prodromou, C. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.07.020 · Cited by 171
“A previously described mutation T22I, originally isolated as a temperature sensitive mutation in yeast [87], was shown to increase the ATPase activity of Hsp90 [9].”
BackgroundUbc9 Interacts with the Androgen Receptor and Activates Receptor-dependent Transcription
Poukka, H., Aarnisalo, P., Karvonen, U., Palvimo, J. J., & Jänne, O. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.27.19441 · Cited by 174
Millson, S. H., Truman, A. W., King, V., Prodromou, C., Pearl, L. H., & Piper, P. W. (2005) · Eukaryotic Cell · doi:10.1128/ec.4.5.849-860.2005 · Cited by 172
Review: The HSP90 molecular chaperone—an enigmatic ATPase
Pearl, L. H. (2016) · Biopolymers · doi:10.1002/bip.22835 · Cited by 178
Hsp90 is regulated by a switch point in the C‐terminal domain
Retzlaff, M., Stahl, M., Eberl, H. C., Lagleder, S., Beck, J., Kessler, H., & Büchner, J. (2009) · EMBO Reports · doi:10.1038/embor.2009.153 · Cited by 170
“A S. cerevisiae strain, carrying an HSC82/ HSP82 double knockout mutation (Nathan & Lindquist, 1995), was transfected with HSP90 variants, cloned in the high-copy vector pRS423 (2 m) and co-transfected with V-SRC present on a vector carrying a URA3 marker.”
BackgroundMethodInfluentialFreeman, B. C., Felts, S. J., Toft, D. O., & Yamamoto, K. R. (2000) · Genes & Development · doi:10.1101/gad.14.4.422 · Cited by 168
Youker, R. T., Walsh, P., Beilharz, T. H., Lithgow, T. J., & Brodsky, J. L. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-07-0584 · Cited by 167
“Similar results were obtained when CFTR degradation in the G170D hsp82 mutant was examined (unpublished data), which also rapidly loses activity at the nonpermissive temperature (Nathan and Lindquist, 1995).”
ResultStructure of Hsp90–p23–GR reveals the Hsp90 client-remodelling mechanism
Noddings, C. M., Wang, R. Y.-R., Johnson, J. L., & Agard, D. A. (2022) · Nature · doi:10.1038/s41586-021-04236-1 · Cited by 164
Mollapour, M., Tsutsumi, S., Truman, A. W., Xu, W., Vaughan, C. K., Beebe, K., Konstantinova, A., Vourganti, S., Panaretou, B., Piper, P. W., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.011 · Cited by 165
“More than a decade ago, in a random mutagenesis study of Hsp90, Lindquist’s group identified the adjacent amino acid T22 as an important determinant of Hsp90 function (Nathan and Lindquist, 1995).”
BackgroundInfluentialPratt, W. B., Silverstein, A. M., & Galigniana, M. D. (1999) · Cellular Signalling · doi:10.1016/s0898-6568(99)00064-9 · Cited by 164
The Hsp90 complex—a super-chaperone machine as a novel drug target
Scheibel, T., & Büchner, J. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00120-8 · Cited by 164
Dittmar, K. D., Banach, M., Galigniana, M. D., & Pratt, W. B. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.13.7358 · Cited by 162
Modulation of the Hsp90 Chaperone Cycle by a Stringent Client Protein
Lorenz, O. R., Freiburger, L., Rutz, D. A., Krause, M., Zierer, B. K., Alvira, S., Cuéllar, J., Valpuesta, J. M., Madl, T., Sattler, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.02.003 · Cited by 151
“For GR, we found several residues, including E381, E431, E507, and T511 in the Hsp90-M domain (Figure 6D), whose mutation had resulted in decreased GR function in vivo (Bohen and Yamamoto, 1993; Genest et al., 2013; Nathan and Lindquist, 1995).”
BackgroundMethodInfluentialThe Charged Linker Region Is an Important Regulator of Hsp90 Function*
Hainzl, O., Lapina, M. C., Buchner, J., & Richter, K. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.031658 · Cited by 150
Interaction of Radicicol with Members of the Heat Shock Protein 90 Family of Molecular Chaperones
Schulte, T. W., Akinaga, S., Murakata, T., Agatsuma, T., Sugimoto, S., Nakano, H., Lee, Y. S., Simen, B. B., Argon, Y., Felts, S. J., et al. (1999) · Molecular Endocrinology · doi:10.1210/mend.13.9.0339 · Cited by 162
The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90
Wandinger, S. K., Suhre, M. H., Wegele, H., & Büchner, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600930 · Cited by 160
“…the yHsp90 system is functional, v-Src passes through the chaperone cycle and reaches its native conformation, which can be monitored by the detection of the autophosphorylation of v-Src with an antibody specific for phosphotyrosine residues in an immunoblot experiment (Nathan and Lindquist, 1995).”
BackgroundMethodInfluentialSBA1 Encodes a Yeast Hsp90 Cochaperone That Is Homologous to Vertebrate p23 Proteins
Fang, Y., Fliss, A., Rao, J., & Caplan, A. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.3727 · Cited by 152
A novel Sec18p/NSF-dependent complex required for Golgi-to-endosome transport in yeast.
Burd, C. G., Peterson, M. R., Cowles, C. R., & Emr, S. D. (1997) · Molecular Biology of the Cell · doi:10.1091/mbc.8.6.1089 · Cited by 151
Adapting to stress — chaperome networks in cancer
Joshi, S., Wang, T., Araujo, T. L. S., Sharma, S., Brodsky, J. L., & Chiosis, G. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0020-9 · Cited by 145
Morra, G., Verkhivker, G. M., & Colombo, G. (2009) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1000323 · Cited by 150
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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