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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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
Steroid receptor interactions with heat shock protein and immunophilin chaperones.
William B. Pratt,David O. Toft +1 more
TL;DR: A historical perspective on a body of steroid receptor research dealing with the structure and physiological significance of the untransformed 9S receptor is provided, and it is shown that hsp90 itself exists in a variety of native multiprotein heterocomplexes independent of steroid receptors and other 'substrate' proteins.
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The Conformational Plasticity of Protein Kinases
TL;DR: Crystal structures of inactive kinases have revealed a remarkable plasticity in the kinase domain that allows the adoption of distinct conformations in response to interactions with specific regulatory domains or proteins.
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An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor
TL;DR: It is found that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine in the activation loop, which suggests that the Kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation.
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Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent
TL;DR: The structure of the geldanamycin-binding domain of Hsp90 reveals a pronounced pocket that is highly conserved across species, and the pocket's similarity to substrate-binding sites suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/refolding reaction.
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Hsp90 as a capacitor of phenotypic variation
TL;DR: It is reported that, in Arabidopsis accessions and recombinant inbred lines, reducing Hsp90 function produces an array of morphological phenotypes, which are dependent on underlying genetic variation, and that HSp90 influences morphogenetic responses to environmental cues and buffers normal development from destabilizing effects of stochastic processes.