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
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AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol
TL;DR: The data delineate a novel link between AMPK, the energy sensor, and HIF-1, the major driver of ATP production, indicating that specifically inhibiting HDAC5 may selectively suppress the survival and proliferation of hypoxic tumor cells.
Journal ArticleDOI
Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative disease- linked proteins
TL;DR: It is established that potentiated Hsp104 variants possess broad substrate specificity and, in yeast, suppress toxicity and aggregation induced by wild-type TDP-43, FUS and α-synuclein, as well as missense mutant versions of these proteins that cause neurodegenerative disease.
Journal ArticleDOI
Importance of cycle timing for the function of the molecular chaperone Hsp90
Bettina K. Zierer,Martin Rübbelke,Franziska Tippel,Tobias Madl,Tobias Madl,Florian H. Schopf,Daniel A. Rutz,Klaus Richter,Michael Sattler,Johannes Buchner +9 more
TL;DR: It was showed that it is crucial for Hsp90 to attain and spend time in certain conformational states: a certain dwell time in open states is required for optimal processing of client proteins, whereas a prolonged population of closed states has negative effects.
Journal ArticleDOI
Developing specific molecular biomarkers for thermal stress in salmonids.
Arash Akbarzadeh,Oliver P. Günther,Aimee Lee S. Houde,Shaorong Li,Tobi J. Ming,Ken M. Jeffries,Scott G. Hinch,Kristina M. Miller +7 more
TL;DR: The results of both discovery analysis and gene expression showed that a panel of genes involved in chaperoning and protein rescue, oxidative stress, and protein biosynthesis were differentially activated in gill tissue of Pacific salmon in response to elevated temperatures.
Journal ArticleDOI
On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms
Mark L. Siegal,Jun-Yi Leu +1 more
TL;DR: This review aims to synthesize current understanding of robustness mechanisms and to cut through the controversy by shedding light on what is and is not known about mutational robustness, and concludes that a profitable way forward is to focus investigations less on mutATIONAL robustness and more on epistasis.
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.