Journal ArticleDOI
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
TLDR
Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.Abstract:
Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.read more
Citations
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Journal ArticleDOI
Molecular chaperones in protein folding and proteostasis
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
Journal ArticleDOI
The Heat Shock Response: Life on the Verge of Death
TL;DR: This Review summarizes the concepts of the protective Hsp network, and the most conserved Hsps are molecular chaperones that prevent the formation of nonspecific protein aggregates and assist proteins in the acquisition of their native structures.
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Combining immunotherapy and targeted therapies in cancer treatment
TL;DR: Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.
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Molecular Chaperone Functions in Protein Folding and Proteostasis
TL;DR: This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
Journal ArticleDOI
In vivo aspects of protein folding and quality control
TL;DR: A new view of protein folding is emerging, whereby the energy landscapes that proteins navigate during folding in vivo may differ substantially from those observed during refolding in vitro.
References
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Journal ArticleDOI
The Hsp70 chaperone machines of Escherichia coli: a paradigm for the repartition of chaperone functions
TL;DR: Genetic and biochemical analyses have greatly expanded knowledge of chaperone tasking in Escherichia coli K‐12, and recent advances in structure determination have led to significant insights of the underlying complexities and functional elegance of the Hsp70 chaperones machine.
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Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins.
TL;DR: It is shown that L858R and deletion mutant EGFR proteins found in NSCLC interact with the chaperone and are sensitive to degradation following Hsp90 inhibition, suggesting mutational activation of EGFR is associated with dependence on HSp90 for stability and that Hsp 90 inhibition may represent a novel strategy for the treatment of EG FR-mutant NSCLCs.
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Specific Binding of Tetratricopeptide Repeat Proteins to the C-terminal 12-kDa Domain of hsp90
TL;DR: The results identify the C90 domain as the specific binding site for a set of hsp90 cofactors having TPR domains.
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Hsp90 chaperonins possess ATPase activity and bind heat shock transcription factors and peptidyl prolyl isomerases.
TL;DR: It is shown that E. coli HtpG immobilized to Affi-Gel beads selectively retains sigma 32 while the yeast and rat hsp90 retain HSF, and the peptidyl prolyl isomerase hsp59 of the FK506 binding class is known to bind to hsp 90.
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Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin.
Silvy da Rocha Dias,Frank Friedlos,Yvonne Light,Caroline J. Springer,Paul Workman,Richard Marais +5 more
TL;DR: The data show that B-RAF is an important target for 17-AAG in human cancer, and it is shown that (V600E)B-RAf is an Hsp90 client protein that requires HSp90 for its folding and stability.