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
Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease
TL;DR: The circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence are reviewed, which represent a minute fraction of fungal diversity.
Journal ArticleDOI
Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms.
TL;DR: The protein quality control systems of the eukaryotic cytosol and the endoplasmic reticulum are compared, focusing on the principles of damage recognition, the triage decisions between chaperone-mediated refolding and proteolytic elimination of damaged proteins, the repair of misfolded and aggregated protein species, and the mechanisms by which perturbations of protein homeostasis are sensed to induce compartment-specific stress responses.
Journal ArticleDOI
The Hsp90 chaperone machinery: Conformational dynamics and regulation by co-chaperones
TL;DR: Hsp90 is a dimeric molecular chaperone required for the activation and stabilization of numerous client proteins many of which are involved in essential cellular processes like signal transduction pathways and regulation by ATP-induced large conformational changes, co-chaperones and posttranslational modifications.
Journal ArticleDOI
Identification of HSP90 inhibitors as a novel class of senolytics
Heike Fuhrmann-Stroissnigg,Yuan Yuan Ling,Jing Zhao,Sara J. McGowan,Yi Zhu,Robert W. Brooks,Diego Grassi,Siobhán Q. Gregg,Jennifer L. Stripay,Akaitz Dorronsoro,Lana Corbo,Priscilla Tang,Christina Bukata,Nadja Ring,Mauro Giacca,Xuesen Li,Tamara Tchkonia,James L. Kirkland,Laura J. Niedernhofer,Paul D. Robbins +19 more
TL;DR: Treatment of Ercc1−/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression, demonstrating the utility of a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells.
Journal ArticleDOI
Cellular Strategies of Protein Quality Control
TL;DR: The spatial and temporal organization of cellular quality control strategies and their implications for human diseases linked to protein misfolding and aggregation are discussed.
References
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Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
Paul T C Wan,Mathew J. Garnett,S. Mark Roe,Sharlene Lee,Dan Niculescu-Duvaz,Valerie M. Good,Cancer Genome,C. Michael Jones,Christopher J. Marshall,Caroline J. Springer,David Barford,Richard Marais +11 more
TL;DR: The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
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HSP90 and the chaperoning of cancer.
TL;DR: Pharmacologically 'bribing' the essential guard duty of the chaperone HSP90 (heat-shock protein of 90 kDa) seems to offer a unique anticancer strategy of considerable promise.
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Hsp90 as a capacitor for morphological evolution
TL;DR: It is reported that when Drosophila Hsp90 is mutant or pharmacologically impaired, phenotypic variation affecting nearly any adult structure is produced, with specific variants depending on the genetic background and occurring both in laboratory strains and in wild populations.
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Adapting proteostasis for disease intervention.
TL;DR: The proteostasis network is described, a set of interacting activities that maintain the health of proteome and the organism that has the potential to ameliorate some of the most challenging diseases of this era.
Journal ArticleDOI
Function and regulation of cullin-RING ubiquitin ligases.
TL;DR: This review focuses on the composition, regulation and function of cullin–RING ligases, and describes how these enzymes can be characterized by a set of general principles.