Heat shock protein 90: its inhibition and function
TLDR
The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations.Abstract:
The molecular chaperone heat shock protein 90 (Hsp90) facilitates metastable protein maturation, stabilization of aggregation-prone proteins, quality control of misfolded proteins and assists in keeping proteins in activation-competent conformations. Proteins that rely on Hsp90 for function are delivered to Hsp90 utilizing a co-chaperone-assisted cycle. Co-chaperones play a role in client transfer to Hsp90, Hsp90 ATPase regulation and stabilization of various Hsp90 conformational states. Many of the proteins chaperoned by Hsp90 (Hsp90 clients) are essential for the progression of various diseases, including cancer, Alzheimer's disease and other neurodegenerative diseases, as well as viral and bacterial infections. Given the importance of these clients in different diseases and their dynamic interplay with the chaperone machinery, it has been suggested that targeting Hsp90 and its respective co-chaperones may be an effective method for combating a large range of illnesses.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.read more
Citations
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Journal ArticleDOI
Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study.
Hana Štorkánová,Sabína Oreská,Maja Špiritović,B. Heřmánková,Kristýna Bubová,Martin Komarc,Karel Pavelka,Jiří Vencovský,Jörg H W Distler,Ladislav Šenolt,Radim Bečvář,Michal Tomcik +11 more
TL;DR: In this paper, the authors evaluated plasma heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc) and characterized its association with SSc-related features.
Journal ArticleDOI
Structure, Function, and Regulation of the Hsp90 Machinery
TL;DR: Recent structural and mechanistic progress in defining the function of organelle-specific and cytosolic Hsp90 is summarized, including the impact of individual cochaperones on the maturation of specific clients and complexes with clients as well as ways of exploiting HSp90 as a drug target.
Journal ArticleDOI
Heat-Shock Proteins in Neuroinflammation.
TL;DR: The role of neuroinflammation in acute and chronic pathological conditions affecting the brain is summarized and the existing literature on HSP-mediated inflammatory function within the central nervous system is explored.
Journal ArticleDOI
Hsp90 inhibitors suppress P53 phosphorylation in LPS - induced endothelial inflammation.
TL;DR: The present results support previous observations on the protective role of P53 against inflammation and clarify mechanisms that govern vascular barrier function.
Journal ArticleDOI
Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective
Adrienne L. Edkins,John T. Price,A. Graham Pockley,Gregory L. Blatch,Gregory L. Blatch,Gregory L. Blatch +5 more
TL;DR: Therapeutic insights from established research on HSPs in cancer and other non-communicable disorders are drawn on, with an emphasis on how the intracellular function of H SPs contrasts with their extracellular properties and function, and their potential diagnostic and therapeutic value to the prevention, management and treatment of chronic diseases.
References
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Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation.
TL;DR: It is demonstrated that HSP participation in multimolecular complex formation is required for src-mediated transformation and can provide a target for drug modulation.
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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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Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin
S.M. Roe,Chrisostomos Prodromou,Ronan O'Brien,John E. Ladbury,Peter W. Piper,Laurence H. Pearl +5 more
TL;DR: Crystal structure determinations of Hsp90 N-terminal domain complexes with geldanamycin and radicicol identify key aspects of their nucleotide mimicry and suggest a rational basis for the design of novel antichaperone drugs.
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ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone in vivo
Barry Panaretou,Chrisostomos Prodromou,S. Mark Roe,Ronan O'Brien,John E. Ladbury,Peter W. Piper,Laurence H. Pearl +6 more
TL;DR: This work demonstrates in vitro an inherent ATPase activity in both yeast Hsp90 and the Escherichia coli homologue HtpG, which is sensitive to inhibition by the Hsp 90‐specific antibiotic geldanamycin, and suggests an ATP‐coupled chaperone cycle for HSp90‐mediated protein folding.
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GHKL, an emergent ATPase/kinase superfamily.
Rinku Dutta,Masayori Inouye +1 more
TL;DR: A novel ATP-binding superfamily that includes diverse protein families such as DNA topoisomerase II, molecular chaperones Hsp90, DNA-mismatch-repair enzymes MutL and histidine kinases is recognition.