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
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
Kliment A. Verba,Ray Yu-Ruei Wang,Akihiko Arakawa,Yanxin Liu,Mikako Shirouzu,Shigeyuki Yokoyama,David A. Agard +6 more
TL;DR: A 3.9 angstrom cryo–electron microscopy structure of the Hsp90-Cdc37-Cdk4 kinase complex is determined and a unifying conceptual and mechanistic models of chaperone-kinase interactions are proposed.
Journal ArticleDOI
A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways
Mikko Taipale,George Tucker,Jian Peng,Irina Krykbaeva,Zhen Yuan Lin,Brett Larsen,Hyungwon Choi,Bonnie Berger,Anne-Claude Gingras,Anne-Claude Gingras,Susan Lindquist,Susan Lindquist +11 more
TL;DR: It is established that NUDC family cochaperones specifically associate with structurally related but evolutionarily distinct β-propeller folds, providing a framework for deciphering the proteostasis network and its regulation in development and disease and expand the use of chaperones as sensors for drug-target engagement.
Journal ArticleDOI
An integrated view of cisplatin-induced nephrotoxicity and ototoxicity.
TL;DR: Cisplatin is one of the most widely-used drugs to treat cancers, but its nephrotoxic and ototoxic side-effects remain major clinical limitations.
Journal ArticleDOI
Glucocorticoid Receptor Function Regulated by Coordinated Action of the Hsp90 and Hsp70 Chaperone Cycles
TL;DR: It is revealed that Hsp70, known to facilitate client delivery to Hsp90, inactivates GR through partial unfolding, whereas HSp90 reverses this inactivation, and surprisingly, Hsp 90 ATP hydrolysis appears to regulate client transfer from HSp70, likely through a coupling of the two chaperone's ATP cycles.
Journal ArticleDOI
Chaperone-mediated autophagy is involved in the execution of ferroptosis.
Zheming Wu,Yang Geng,Xiaojuan Lu,Yuying Shi,Guowei Wu,Mengmeng Zhang,Bing Shan,Heling Pan,Junying Yuan +8 more
TL;DR: This study identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis, and found that HSP90 defined a common regulatory nodal between necroPTosis and ferroPTosis.
References
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Journal ArticleDOI
Mechanism of Activation of the Raf-Erk Signaling Pathway by Oncogenic Mutations of B-Raf
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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.