Structural and functional reconstitution of the glucocorticoid receptor-hsp90 complex.

Scherrer, Lawrence C.; Dalman, Friedrich C.; Massa, Enrique; Meshinchi, Soheil; Pratt, William B.

doi:10.1016/s0021-9258(18)45746-8

Cited by 180 publications

(38 citation statements)

References 24 publications

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“…In the case of the glucocorticoid receptor, interactions of receptor with microtubules in human gingival fibroblasts (2) and with actin in hepatoma cells (27) were observed by immunocytochemical methods (2) and by subcellular fractionation (27). The distribution of hsp90 has also been studied, since this protein is associated with steroid hormone receptors (5,34,37,38,41). Interactions between hspg0 and tubulin (33,36), or hspg0 and actin (20) have recently been reported.…”

Section: Discussionmentioning

confidence: 99%

The cytoskeleton and the cellular traffic of the progesterone receptor.

Perrot‐Applanat

Lescop

Milgröm

1992

The Journal of Cell Biology

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Abstract. Previous studies on glucocorticoid receptorshave suggested the existence of interactions between the receptor and microtubule or actin networks. It was hypothesized that such interactions may contribute to the guidance of steroid hormone receptors towards the nucleus.We used a permanent L cell line expressing the A638-642 progesterone receptor. This mutant has all the characteristics of the wild type receptor except that the deletion of five amino acids inactivates the constitutive karyophilic signal. Consequently, the receptor is cytoplasmic in the absence of hormone but is shifted into the nucleus when administration of hormone activates the second karyophilic signal. Optical microscopy and confocal laser microscopy were used in intact cells or in cells depleted of soluble elements by permeabilization with detergents. By immunofluorescence, the receptor was found to be mainly concentrated in the perinuclear area. A small fraction of progesterone receptor (PR) persisted in this region after Triton X100 treatment. These observations suggested that the receptor could interact with some insoluble constituent(s) of the cytoplasm. However, careful colocalization studies showed that this heterogenous distribution was not due to interactions with microtubule, microfilament, or intermediate filament networks.Functional involvement of these networks in the translocation of the receptor into the nucleus was studied after cell treatment with cytoskeletal drugs such as nocodazole, demecolcine and cytochalasin. None of these compounds prevented or even delayed the hormone-dependent transfer of A638-642 PR into the nucleus. Similar conclusions were reached with the wild type receptor expressed by transfection in Cos-7 cells. PR was shifted from the nucleus into the cytoplasm by administration of energy-depleting drugs. After disruption of the various cytoskeletal networks normal nuclear reaccumulation of the receptor was observed when these drugs were removed.The results thus suggest that the progesterone receptor is not colocalized with the main cytoskeletal components. Disruption of the cytoskeletal networks does not prevent its nuclear translocation. Thus, karyophilic signals and interactions with the nuclear pore seem to be the primary determinants of the cellular traffic of the progesterone receptor.

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Section: Discussionmentioning

confidence: 99%

The cytoskeleton and the cellular traffic of the progesterone receptor.

Perrot‐Applanat

Lescop

Milgröm

1992

The Journal of Cell Biology

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“…If misfolded protein increases such that the levels of available chaperones become limiting, a greater fraction of that chaperone clients will be unbound and consequently misfolded. Our strategy to quantify Hsp90 availability was thus to measure the folding state of a well-studied client protein of Hsp90, glucocorticoid receptor (GR; Scherrer et al, 1990). Though not an endogenous yeast protein, the mammalian gene has been demonstrated to retain its Hsp90-dependent activity in yeast cells (Kimura et al, 1995).…”

Section: Fluorescent Reporters Quantitatively Measure Hsp90 Availability and Hsr Activationmentioning

confidence: 99%

Quantification of Hsp90 availability reveals differential coupling to the heat shock response

Alford

Brandman

2018

Journal of Cell Biology

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“…Conditions (e.g., salt) that cause Hsp90 to dissociate eliminate the steroid-binding capacity of the GR, even if it is kept at 0 C. 10 The Hsp90-free GR can be converted back to the Hsp90-bound form by incubating it with reticulocyte lysate, and this is accompanied by restoration of steroidbinding activity. 11 There is a linear relationship between the number of GR-Hsp90 heterocomplexes that are assembled in this cell-free system and the amount of steroid-binding activity. 12 Subsequently, it was shown that only the Hsp90-Hop-Hsp70 core machinery is required to open the ligand-binding cleft to allow steroid binding, 13 but that the Hsp90 co-chaperone p23 is required for stable GR-Hsp90 heterocomplex assembly.…”

Section: Introductionmentioning

confidence: 97%

A model in which heat shock protein 90 targets protein-folding clefts: Rationale for a new approach to neuroprotective treatment of protein folding diseases

Pratt

Morishima

Gestwicki

et al. 2014

Exp Biol Med (Maywood)

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In an EBM Minireview published in 2010, we proposed that the Hsp90/Hsp70-based chaperone machinery played a major role in determining the selection of proteins that have undergone oxidative or other toxic damage for ubiquitination and proteasomal degradation (1). The proposal was based on a model in which the Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts (2). The model provides a framework for thinking about the development of neuroprotective therapies for protein folding diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD) and the polyglutamine expansion disorders, such as Huntington’s disease (HD) and spinal and bulbar muscular atrophy (SBMA). Major aberrant proteins that misfold and accumulate in these diseases are ‘client’ proteins of the abundant and ubiquitous stress chaperone Hsp90 (3). These Hsp90 client proteins include tau (AD), α-synuclein (PD), huntingtin (HD) and the expanded glutamine androgen receptor (polyQ AR) (SBMA). In this minireview we update our model in which Hsp90 acts on protein folding clefts and show how it forms a rational basis for developing drugs that promote the targeted elimination of these aberrant proteins.

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Structural and functional reconstitution of the glucocorticoid receptor-hsp90 complex.

Cited by 180 publications

References 24 publications

The cytoskeleton and the cellular traffic of the progesterone receptor.

The cytoskeleton and the cellular traffic of the progesterone receptor.

Quantification of Hsp90 availability reveals differential coupling to the heat shock response

A model in which heat shock protein 90 targets protein-folding clefts: Rationale for a new approach to neuroprotective treatment of protein folding diseases

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