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
Ligand-Induced Conformational Changes in HSP90 Monitored Time Resolved and Label Free-Towards a Conformational Activity Screening for Drug Discovery.
Jörn Güldenhaupt,Marta Amaral,Carsten Kötting,Jonas Schartner,Djordje Musil,Matthias Frech,Klaus Gerwert +6 more
TL;DR: This work immobilized the heat shock protein HSP90 on an ATR crystal, an important molecular target for drugs against several diseases including cancer, and investigated a ligand‐induced secondary structural change.
Journal ArticleDOI
HSP90 Inhibitor Geldanamycin as a Radiation Response Modificator in Human Blood Cells.
TL;DR: By significantly up-regulating catalase levels over the entire range of doses from 0.5 to 4 Gy, the inhibitor of Hsp90 exerted adaptive protection and modified the early radiation response of the human blood cells.
Journal ArticleDOI
Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model.
TL;DR: It is demonstrated that HER2 expression was inhibited at the post-transcriptional level in these immune-resistant cells, suggesting that tumor cells may escape antitumor immunity through thePost-Transcriptional regulation of antigen gene expression.
Journal ArticleDOI
Mitochondrial compartmentalized protein folding and tumor cell survival.
TL;DR: Fresh experimental evidence has now uncovered a role for mitochondrial localized chaperones to oversee the protein folding environment within the organelle, selectively in tumor cells.
Journal ArticleDOI
Disease Variants of FGFR3 Reveal Molecular Basis for the Recognition and Additional Roles for Cdc37 in Hsp90 Chaperone System
Tom D. Bunney,Alison J. Inglis,Domenico Sanfelice,Brendan Farrell,Christopher J. Kerr,Gary S. Thompson,Glenn R. Masson,Nethaji Thiyagarajan,Dmitri I. Svergun,Roger L. Williams,Alexander L. Breeze,Matilda Katan +11 more
TL;DR: It is shown that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface.
References
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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.