The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo

Riggs, Daniel L.; Roberts, Patricia J.; Chirillo, Samantha C.; Cheung‐Flynn, Joyce; Prapapanich, Viravan; Ratajczak, Thomas; Gaber, Richard F.; Picard, Didier; Smith, David F.

doi:10.1093/emboj/cdg108

Cited by 322 publications

(393 citation statements)

References 59 publications

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“…The diagrams in Figure 8 detail the minimal systems required for activation, but numerous other co-chaperones have been identified and are believed to play important roles in the regulation of the chaperone cycle in vivo (Table 2). For example, the immunophilin FKBP52 is found in complex with Hsp90, GR/PR, and p23 in vivo; FKBP52 also increases the hormone binding ability of GR and is essential for the correct activation of PR in vivo (Chadli et al, 2008;Riggs et al, 2003).While some co-chaperones such as Hsp70 and Hsp40 are required for client recruitment, other co-chaperones regulate both the ATPase activity and the conformational dynamics of Hsp90.…”

Section: The Role Of Co-chaperones In Regulating the Conformational Cmentioning

confidence: 99%

“…Aha1 stimulates ATPase activity * p50 blocks ATPase activity and is thought to be kinase specific * Cpr6 TPR-containing and peptidy-prolyl-isomerase (Johnson et al, 2007) FKBP52 TPR-containing and peptidy-prolyl-isomerase (Riggs et al, 2003) GCUNC-45 TPR-containing that blocks progression of cycle (Chadli et al, 2006) Hop TPR-containing and scaffolds Hsp70-Hsp90 interaction * Hsp70 recruits substrates to Hsp90 * NudC CHORD-domain containing (Te et al, 2007) p23 blocks ATPase activity and traps client proteins in complex with Hsp90 * PP5 TPR-containing and phosphatase * Sse1 part of Hsp90 complex in budding yeast (Liu et al, 1999) Tah1 TPR-containing For a list of additional co-chaperones see http://www.picard.ch/downloads/Hsp90interactors.pdf * References can be found in the text.…”

Section: Protein Functionmentioning

confidence: 99%

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Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

278

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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Section: The Role Of Co-chaperones In Regulating the Conformational Cmentioning

confidence: 99%

Section: Protein Functionmentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

278

262

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“…32 Upon hormone stimulation, there is a switch from FKBP51 to the closely related TPR protein, FKBP52, which positively regulates GR activity. 5,7,8 Therefore, we analyzed whether impairment of SUMO conjugation to FKBP51 alters the cochaperone composition of this complex. Figure 5d shows that wt FKBP51 and not K422R mutant is associated to the GR, thus corroborating our previous results.…”

Section: Resultsmentioning

confidence: 99%

“…6 Ligand binding to the GR induces an exchange between FKBP51 and the closely related TPR protein FKBP52, 7 which in turn enhances GR activity. 8 Abnormal FKBP51 function has been implicated in a wide variety of diseases, in particular stress-related disorders associated with impaired GR signaling. 2,9 Interestingly, it has also been suggested that FKBP51 might be involved in changes in hippocampal plasticity and alterations in its structure, with a final impact on the response to stress.…”

mentioning

confidence: 99%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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“…23 Studies analyzing protein expression levels showed that FKBP-52 potentiates reporter gene activation, which is attenuated by FKBP-51. 8,24 We hypothesized that the ratio of FKBP-51 and FKBP-52 mRNA levels is related to GC resistance. As we could not show such a correlation in our study population, and as we did not show a relation between FKBP-51 mRNA expression and GC resistance either, the relevance of FKBP-51 for GC resistance as found in some New World primates cannot be extrapolated to GC resistance in childhood ALL.…”

Section: Figurementioning

confidence: 99%

mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL

et al. 2005

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Resistance to glucocorticoids (GC) is an important adverse risk factor in the treatment of acute lymphoblastic leukemia (ALL). To induce apoptosis, GC bind to the GC receptor (GR), which is regulated by various (co)chaperone proteins such as heatshock protein 70 (HSP-70), HSP-40, HIP (HSP-70-interacting protein), BAG-1 (BCL-2-associated gene product-1), HOP (HSP-70/HSP-90-Organizing protein), HSP-90, P-23, FKBP-51, FKBP-52 and CYP-40. In this study, we tested the hypothesis that mRNA expression levels of these molecules are determinants of GC resistance in childhood ALL. In all, 20 children with ALL cells in vitro sensitive to prednisolone (LC 50 o0.1 lg/ml) were compared each with a resistant patient (LC 50 4150 lg/ml), matched for immunophenotype, age and white blood cell count. mRNA expression levels of the (co)chaperone molecules were measured by quantitative real-time RT-PCR and normalized to GAPDH and RNaseP levels. In vitro resistance to prednisolone was measured by MTT assay. HSP-90 mRNA expression levels were 2000-fold higher as compared to HSP-70. Using matched pair analysis, mRNA expression levels of the various (co)chaperone molecules were not significantly different between in vitro-sensitive and -resistant patients. GC resistance in childhood ALL cannot be attributed to different mRNA expression levels of the investigated (co)chaperone molecules involved in GC binding and transport to the nucleus.

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The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo

Cited by 322 publications

References 59 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL

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