C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances
Petr Müller,Eva Ruckova,Petr Halada,Philip J. Coates,Roman Hrstka,David P. Lane,Borek Vojtesek +6 more
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TLDR
The data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-Chaperone expression and chaperone modifications.Abstract:
Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-β in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non-phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment.read more
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Structure, Function and Regulation of the Hsp90 Machinery
Jing Li,Johannes Buchner +1 more
TL;DR: The recent progress made in understanding the Hsp90 machinery is discussed, which influences the conformational cycle, co-chaperone interaction, and inter-domain communications.
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Mechanisms of Hsp90 regulation.
TL;DR: This review, looks at the many different levels by which Hsp90 activity is ultimately regulated and some are directly responsible for delivery of client protein.
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The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis.
Uwe Knippschild,Marc Krüger,Julia Richter,Pengfei Xu,Balbina García-Reyes,Christian Peifer,Jakob Halekotte,Vasiliy A. Bakulev,Joachim Bischof +8 more
TL;DR: In this paper, the authors summarized the current knowledge regarding the regulation, functions, and interactions of CK1 family members with cellular proteins playing central roles in cellular stress-responses and carcinogenesis.
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Hsp90 interaction with clients
TL;DR: The emerging model is that the Hsp90 ATPase does not modulate client affinity but instead controls substrate influx from Hsp70, ensuring that clients preferentially bind to Hsp 70 early on in the folding path, but downstream folding intermediates bind Hsp 90.
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Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis
Andrija Finka,Pierre Goloubinoff +1 more
TL;DR: A meta-analysis of human chaperome is performed using high-throughput proteomic data from 11 immortalized human cell lines to understand mechanisms by which the Hsp60, Hsp70, HSPs, and small heat shock proteins, in collaboration with cochaperones and folding enzymes, assist de novo protein folding, import polypeptides into organelles, unfold stress-destabilized toxic conformers, and control the conformal activity of native proteins in the
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