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Johannes Buchner - One of the best experts on this subject based on the ideXlab platform.
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a chemical compound inhibiting the aha1 hsp90 chaperone complex
Journal of Biological Chemistry, 2017Co-Authors: Sandrine C Stiegler, Martin Rubbelke, Vadim S Korotkov, Matthias Weiwad, Christine John, Gunter Fischer, Stephan A Sieber, Michael Sattler, Johannes BuchnerAbstract:Abstract The eukaryotic Hsp90 chaperone machinery comprises many Co-Chaperones and regulates the conformation of hundreds of cytosolic client proteins. Therefore, it is not surprising that the Hsp90 machinery has become an attractive therapeutic target for diseases such as cancer. The compounds used so far to target this machinery affect the entire Hsp90 system. However, it would be desirable to achieve a more selective targeting of Hsp90-Co-Chaperone complexes. To test this concept, in this-proof-of-principle study, we screened for modulators of the interaction between Hsp90 and its Co-Chaperone Aha1, which accelerates Hsp90's ATPase activity. A FRET-based assay that monitored Aha1 binding to Hsp90 enabled identification of several chemical compounds modulating the effect of Aha1 on Hsp90 activity. We found that one of these inhibitors can abrogate the Aha1-induced ATPase stimulation of Hsp90 without significantly affecting Hsp90 ATPase activity in the absence of Aha1. NMR spectroscopy revealed that this inhibitory compound binds the N-terminal domain of Hsp90 close to its ATP-binding site and overlapping with a transient Aha1-interaction site. We also noted that this inhibitor does not dissociate the Aha1-Hsp90 complex but prevents the specific interaction with the N-terminal domain of Hsp90 required for catalysis. In consequence, the inhibitor affected the activation and processing of Hsp90-Aha1-dependent client proteins in vivo. We conclude that it is possible to abrogate a specific Co-Chaperone function of Hsp90 without inhibiting the entire Hsp90 machinery. This concept may also hold true for other Co-Chaperones of Hsp90.
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a chemical compound inhibiting the aha1 hsp90 chaperone complex
Journal of Biological Chemistry, 2017Co-Authors: Sandrine C Stiegler, Martin Rubbelke, Vadim S Korotkov, Matthias Weiwad, Christine John, Gunter Fischer, Stephan A Sieber, Michael Sattler, Johannes BuchnerAbstract:The eukaryotic Hsp90 chaperone machinery comprises many Co-Chaperones and regulates the conformation of hundreds of cytosolic client proteins. Therefore, it is not surprising that the Hsp90 machinery has become an attractive therapeutic target for diseases such as cancer. The compounds used so far to target this machinery affect the entire Hsp90 system. However, it would be desirable to achieve a more selective targeting of Hsp90–Co-Chaperone complexes. To test this concept, in this-proof-of-principle study, we screened for modulators of the interaction between Hsp90 and its Co-Chaperone Aha1, which accelerates the ATPase activity of Hsp90. A FRET-based assay that monitored Aha1 binding to Hsp90 enabled identification of several chemical compounds modulating the effect of Aha1 on Hsp90 activity. We found that one of these inhibitors can abrogate the Aha1-induced ATPase stimulation of Hsp90 without significantly affecting Hsp90 ATPase activity in the absence of Aha1. NMR spectroscopy revealed that this inhibitory compound binds the N-terminal domain of Hsp90 close to its ATP-binding site and overlapping with a transient Aha1-interaction site. We also noted that this inhibitor does not dissociate the Aha1–Hsp90 complex but prevents the specific interaction with the N-terminal domain of Hsp90 required for catalysis. In consequence, the inhibitor affected the activation and processing of Hsp90–Aha1-dependent client proteins in vivo. We conclude that it is possible to abrogate a specific Co-Chaperone function of Hsp90 without inhibiting the entire Hsp90 machinery. This concept may also hold true for other Co-Chaperones of Hsp90.
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the hsp90 chaperone machinery
Nature Reviews Molecular Cell Biology, 2017Co-Authors: Florian H Schopf, Maximilian M Biebl, Johannes BuchnerAbstract:The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of Co-Chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its Co-Chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
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structural characterization of the substrate transfer mechanism in hsp70 hsp90 folding machinery mediated by hop
Nature Communications, 2014Co-Authors: Soh Yamamoto, Alina Rohl, Sara Alvira, Jorge Cuellar, Hideaki Itoh, Carlos Alfonso, German Rivas, Johannes BuchnerAbstract:Hsp70 and Hsp90 cooperate to fold client proteins, aided by Co-Chaperones such as Hop. Here Alvira et al. determine EM structures of various combinations of Hsp70, Hsp90, Hop and a client protein to shed structural insight into the mechanism of client protein transfer from one chaperone to the other.
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the chaperone hsp90 changing partners for demanding clients
Trends in Biochemical Sciences, 2013Co-Authors: Alina Rohl, Julia Rohrberg, Johannes BuchnerAbstract:The heat shock protein (Hsp)90 chaperone machinery regulates the activity of hundreds of client proteins in the eukaryotic cytosol. It undergoes large conformational changes between states that are similar in energy. These transitions are rate-limiting for the ATPase cycle. It has become evident that several of the many Hsp90 Co-Chaperones affect the conformational equilibrium by stabilizing specific intermediate states. Consequently, there is an ordered progression of different Co-Chaperones during the conformational cycle. Asymmetric complexes containing two different Co-Chaperones may be important for the processing of the client protein, although our understanding of this aspect, as well as the details of the interaction of Hsp90 with client proteins, is still in its infancy.
Len Neckers - One of the best experts on this subject based on the ideXlab platform.
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the double edge of the hsp90 cdc37 chaperone machinery opposing determinants of kinase stability and activity
Future Oncology, 2012Co-Authors: Len NeckersAbstract:Evaluation of: Gaude H, Aznar N, Delay A et al. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumor suppressor LKB1. Oncogene 31(12), 1582–1591 (2012). The molecular chaperone HSP90, in concert with the Co-Chaperone CDC37, facilitates the maturation and modulates the activity of a variety of protein kinases. In this article, Gaude and colleagues described the dual activities of the HSP90–CDC37 chaperone machinery in maintaining the stability while inhibiting the activity of LKB1 kinase. LKB1 in complex with HSP90–CDC37 has a longer half-life but is incapable of autophosphorylation, and its kinase activity is increased upon HSP90 inhibition. Dissociation of HSP90 from LKB1 results in its interaction with HSP/HSC70. HSP/HSC70 recruits the ubiquitin ligase CHIP, which ubiquitinates LKB1, leading to its proteasome-mediated degradation. These data emphasize the versatile roles of molecular chaperones associated with LKB1 and warrant future studies to characte...
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post translational modifications of hsp90 and their contributions to chaperone regulation
Biochimica et Biophysica Acta, 2012Co-Authors: Mehdi Mollapour, Len NeckersAbstract:Molecular chaperones, as the name suggests, are involved in folding, maintenance, intracellular transport, and degradation of proteins as well as in facilitating cell signaling. Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone that carries out these processes in normal and cancer cells. Hsp90 function in vivo is coupled to its ability to hydrolyze ATP and this can be regulated by Co-Chaperones and post-translational modifications. In this review, we explore the varied roles of known post-translational modifications of cytosolic and nuclear Hsp90 (phosphorylation, acetylation, S-nitrosylation, oxidation and ubiquitination) in fine-tuning chaperone function in eukaryotes. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
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chip activates hsf1 and confers protection against apoptosis and cellular stress
The EMBO Journal, 2003Co-Authors: Qian Dai, Douglas M Cyr, Len Neckers, Chunlian Zhang, Holly Mcdonough, Ryan A Whaley, Virginia Godfrey, Nageswara R Madamanchi, Cam PattersonAbstract:Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function Co-Chaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine fibroblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple levels by regulation of protein quality control and transcriptional activation of stress response signaling.
Jason E Gestwicki - One of the best experts on this subject based on the ideXlab platform.
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bag3 is a modular scaffolding protein that physically links heat shock protein 70 hsp70 to the small heat shock proteins
Journal of Molecular Biology, 2017Co-Authors: Jennifer N Rauch, Rebecca Freilich, Leah N Makley, Daniel R Southworth, Jason E GestwickiAbstract:Abstract Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that are important for binding and stabilizing unfolded proteins. In this task, the sHsps have been proposed to coordinate with ATP-dependent chaperones, including heat shock protein 70 (Hsp70). However, it is not yet clear how these two important components of the chaperone network are linked. We report that the Hsp70 Co-Chaperone, BAG3, is a modular, scaffolding factor to bring together sHsps and Hsp70s. Using domain deletions and point mutations, we found that BAG3 uses both of its IPV motifs to interact with sHsps, including Hsp27 (HspB1), αB-crystallin (HspB5), Hsp22 (HspB8), and Hsp20 (HspB6). BAG3 does not appear to be a passive scaffolding factor; rather, its binding promoted de-oligomerization of Hsp27, likely by competing for the self-interactions that normally stabilize large oligomers. BAG3 bound to Hsp70 at the same time as Hsp22, Hsp27, or αB-crystallin, suggesting that it might physically bring the chaperone families together into a complex. Indeed, addition of BAG3 coordinated the ability of Hsp22 and Hsp70 to refold denatured luciferase in vitro. Together, these results suggest that BAG3 physically and functionally links Hsp70 and sHsps.
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pharmacological targeting of the hsp70 chaperone
Current Topics in Medicinal Chemistry, 2009Co-Authors: Srikanth Patury, Yoshinari Miyata, Jason E GestwickiAbstract:The molecular chaperone, heat shock protein 70 (Hsp70), acts at multiple steps in a protein's life cycle, including during the processes of folding, trafficking, remodeling and degradation. To accomplish these various tasks, the activity of Hsp70 is shaped by a host of Co-Chaperones, which bind to the core chaperone and influence its functions. Genetic studies have strongly linked Hsp70 and its Co-Chaperones to numerous diseases, including cancer, neurodegeneration and microbial pathogenesis, yet the potential of this chaperone as a therapeutic target remains largely underexplored. Here, we review the current state of Hsp70 as a drug target, with a special emphasis on the important challenges and opportunities imposed by its Co-Chaperones, protein-protein interactions and allostery.
Cam Patterson - One of the best experts on this subject based on the ideXlab platform.
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chip mediated stress recovery by sequential ubiquitination of substrates and hsp70
Nature, 2006Co-Authors: Shubing Qian, Douglas M Cyr, Frank Boellmann, Holly Mcdonough, Cam PattersonAbstract:Exposure of cells to various stresses often leads to the induction of a group of proteins called heat shock proteins (HSPs, molecular chaperones). Hsp70 is one of the most highly inducible molecular chaperones, but its expression must be maintained at low levels under physiological conditions to permit constitutive cellular activities to proceed. Heat shock transcription factor 1 (HSF1) is the transcriptional regulator of HSP gene expression, but it remains poorly understood how newly synthesized HSPs return to basal levels when HSF1 activity is attenuated. CHIP (carboxy terminus of Hsp70-binding protein), a dual-function Co-Chaperone/ubiquitin ligase, targets a broad range of chaperone substrates for proteasomal degradation. Here we show that CHIP not only enhances Hsp70 induction during acute stress but also mediates its turnover during the stress recovery process. Central to this dual-phase regulation is its substrate dependence: CHIP preferentially ubiquitinates chaperone-bound substrates, whereas degradation of Hsp70 by CHIP-dependent targeting to the ubiquitin-proteasome system occurs when misfolded substrates have been depleted. The sequential catalysis of the CHIP-associated chaperone adaptor and its bound substrate provides an elegant mechanism for maintaining homeostasis by tuning chaperone levels appropriately to reflect the status of protein folding within the cytoplasm.
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chip activates hsf1 and confers protection against apoptosis and cellular stress
The EMBO Journal, 2003Co-Authors: Qian Dai, Douglas M Cyr, Len Neckers, Chunlian Zhang, Holly Mcdonough, Ryan A Whaley, Virginia Godfrey, Nageswara R Madamanchi, Cam PattersonAbstract:Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function Co-Chaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine fibroblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple levels by regulation of protein quality control and transcriptional activation of stress response signaling.
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protein quality control u box containing e3 ubiquitin ligases join the fold
Trends in Biochemical Sciences, 2002Co-Authors: Douglas M Cyr, Jorg Hohfeld, Cam PattersonAbstract:Molecular chaperones act with folding Co-Chaperones to suppress protein aggregation and refold stress damaged proteins. However, it is not clear how slowly folding or misfolded polypeptides are targeted for proteasomal degradation. Generally, selection of proteins for degradation is mediated by E3 ubiquitin ligases of the mechanistically distinct HECT and RING domain sub-types. Recent studies suggest that the U-box protein family represents a third class of E3 enzymes. CHIP, a U-box-containing protein, is a degradatory Co-Chaperone of heat-shock protein 70 (Hsp70) and Hsp90 that facilitates the polyubiquitination of chaperone substrates. These data indicate a model for protein quality control in which the interaction of Hsp70 and Hsp90 with Co-Chaperones that have either folding or degradatory activity helps to determine the fate of non-native cellular proteins.
Marc B. Cox - One of the best experts on this subject based on the ideXlab platform.
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therapeutic targeting of the fkbp52 co chaperone in steroid hormone receptor regulated physiology and disease
Current Molecular Pharmacology, 2015Co-Authors: Naihsuan Guy, Yenni A. Garcia, Marc B. CoxAbstract:Steroid hormone receptors are ligand-dependent transcription factors that require the dynamic, ordered assembly of multimeric chaperone complexes to reach a functional conformation. Heat shock protein (Hsp) 70 and Hsp90 serve as the central chaperones that mediate this process in conjunction with a variety of Co-Chaperones. Many of these cochaperones represent potential therapeutic targets for the disruption of Hsp90 client protein function. FKBP52 is an Hsp90-associated Co-Chaperone that has emerged as a promising therapeutic candidate due to its functional specificity for a small subset of Hsp90 client proteins including androgen (AR), glucocorticoid (GR), and progesterone (PR) receptors. Given its Hsp90-client protein specificity, the targeting of FKBP52 should be more specific and less toxic than the Hsp90- targeting drugs. Additionally, the fkbp52-deficient mice display specific phenotypes related to androgen, progesterone, and glucocorticoid insensitivity suggesting minimal off-target effects. Finally, the fact that FKBP52 is already a validated target of the clinically approved immunosuppressive drug, FK506 (Tacrolimus), indicates that FKBP52 is a "druggable" protein. Thus, the development of FKBP52-specific small molecule inhibitors is predicted to be a highly targeted strategy with potential for the treatment of any disease that is dependent on a functional AR, GR, and/or PR signaling pathway. Much progress has been made in understanding the residues and domains critical for FKBP52 function. The proline-rich loop overhanging the FKBP52 FK1 catalytic domain is functionally important and likely represents an interaction surface within the receptor-chaperone complex. Thus, the targeting of FKBP52 proline-rich loop interactions is the most attractive therapeutic approach to disrupt FKBP52 regulation of receptor activity in steroid hormone receptor-dependent physiology and disease.
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Functions of the Hsp90-binding FKBP immunophilins.
Sub-cellular biochemistry, 2014Co-Authors: Naihsuan Guy, Yenni A. Garcia, Jeffrey C. Sivils, Mario D. Galigniana, Marc B. CoxAbstract:Hsp90 functionally interacts with a broad array of client proteins, but in every case examined Hsp90 is accompanied by one or more Co-Chaperones. One class of Co-Chaperone contains a tetratricopeptide repeat domain that targets the Co-Chaperone to the C-terminal region of Hsp90. Within this class are Hsp90-binding peptidylprolyl isomerases, most of which belong to the FK506-binding protein (FKBP) family. Despite the common association of FKBP Co-Chaperones with Hsp90, it is now clear that the client protein influences, and is influenced by, the particular FKBP bound to Hsp90. Examples include Xap2 in aryl hydrocarbon receptor complexes and FKBP52 in steroid receptor complexes. In this chapter, we discuss the known functional roles played by FKBP Co-Chaperones and, where possible, relate distinctive functions to structural differences between FKBP members.