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
More filters
Journal ArticleDOI
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.
Journal ArticleDOI
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.
Journal ArticleDOI
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
More filters
Journal ArticleDOI
V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors
TL;DR: It is suggested that activated mutated B-Raf proteins are incompetent for folding in the absence of Hsp90, thus suggesting that the chaperone is required for the clonal evolution of melanomas and other tumors that depend on this mutation.
Journal ArticleDOI
Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery.
Philippe Meyer,Chrisostomos Prodromou,Chunyan Liao,Bin Hu,S. Mark Roe,Cara K. Vaughan,Ignacija Vlasic,Barry Panaretou,Peter W. Piper,Laurence H. Pearl +9 more
TL;DR: Structural analysis and mutagenesis show that binding of N‐Aha1 promotes a conformational switch in the middle‐segment catalytic loop of Hsp90 that releases the catalytic Arg 380 and enables its interaction with ATP in the N‐terminal nucleotide‐binding domain of the chaperone.
Journal ArticleDOI
All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae
TL;DR: It is concluded that cyclophilins and FKBPs do not play an essential general role in protein folding and find little evidence of functional overlap between the different enzymes, and it is proposed that each cyclophile and FKBP regulates a restricted number of unique partner proteins that remain to be identified.
Journal ArticleDOI
Hypoxia-induced activation of HIF-1: role of HIF-1α-Hsp90 interaction
Emmanuel Minet,Denis Mottet,Gaetan Michel,Isabelle Roland,Martine Raes,Jean Remacle,Carine Michiels +6 more
TL;DR: It is shown that Hsp90 activity is essential for HIF‐1 activation in hypoxia since it is inhibited in the presence of geldanamycin.
Journal ArticleDOI
Structure of an Hsp90-Cdc37-Cdk4 Complex
Cara K. Vaughan,Ulrich Gohlke,Frank Sobott,Valerie M. Good,Maruf M.U. Ali,Chrisostomos Prodromou,Carol V. Robinson,Helen R. Saibil,Laurence H. Pearl +8 more
TL;DR: An Hsp90-Cdc37-Cdk4 complex is expressed and purified, its stoichiometry is defined, and its 3D structure is determined by single-particle electron microscopy, suggesting a mechanism by which conformational changes in the kinase are coupled to the HSp90 ATPase cycle.