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
Dynamic activation of endothelial nitric oxide synthase by Hsp90
Guillermo García-Cardeña,Guillermo García-Cardeña,Roger Fan,Vijay Shah,Raffaella Sorrentino,Giuseppe Cirino,Andreas Papapetropoulos,William C. Sessa +7 more
TL;DR: Inhibition of signalling through Hsp90 attenuates both agonist-stimulated production of nitric oxide and endothelium-dependent relaxation of isolated blood vessels and indicates that in addition to its role as a molecular chaperone involved in protein folding and maturation, HSp90 may also be recruited to cellular targets depending on the activation state of the cell.
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Structure and Mechanism of the Hsp90 Molecular Chaperone Machinery
TL;DR: Present knowledge of Hsp90 structure and function gleaned from crystallographic studies of individual domains and recent progress in obtaining a structure for the ATP-bound conformation of the intact dimeric chaperone are discussed.
Journal ArticleDOI
The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.
Patrice Connell,Carol A. Ballinger,Jihong Jiang,Yaxu Wu,Larry J. Thompson,Jörg Höhfeld,Jörg Höhfeld,Cam Patterson +7 more
TL;DR: It is shown that CHIP abolishes the steroid-binding activity and transactivation potential of the glucocorticoid receptor, a well-characterized Hsp90 substrate, even though it has little effect on its synthesis.
Journal ArticleDOI
Modulation of Akt kinase activity by binding to Hsp90
TL;DR: Results indicate that Hsp90 plays an important role in maintaining Akt kinase activity by preventing PP2A-mediated dephosphorylation.
Journal ArticleDOI
Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex
Maruf M.U. Ali,S. Mark Roe,Cara K. Vaughan,Phillipe Meyer,Phillipe Meyer,Barry Panaretou,Peter W. Piper,Chrisostomos Prodromou,Laurence H. Pearl +8 more
TL;DR: The structure reveals the complex architecture of the ‘closed’ state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1.