Independent Regulation of Hsp70 and Hsp90 Chaperones by Hsp70/Hsp90-organizing Protein Sti1 (Hop1)

Song, Youtao; Masison, Daniel C.

doi:10.1074/jbc.m505420200

Cited by 102 publications

(107 citation statements)

References 38 publications

(46 reference statements)

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“…Interestingly, we found that 115-7c prolonged the association of both Hsp70 and Hsp90 with Q103. It is not yet clear why Hsp70 and Hsp90 are co-incident in their accumulation because we did not directly detect the co-chaperone, Sti1, which normally links these chaperones (27,29). However, it is possible that the stringency of the washing steps removed this factor or that it is present at low levels.…”

Section: Discussionmentioning

confidence: 66%

“…In addition, Hsp26 works with Hsp104 to help break large fibrils into inheritable fragments (26), while Hsp70 and Hsp90 also assist in this process (27). Some of these shared activities may involve direct interactions between chaperones; for example, Hsp70 binds directly to Hsp104 (28) and Hsp70 and Hsp90 can be physically linked via Sti1 (29). Together, these studies suggest that HSP-class chaperones, especially members of the Hsp26, Hsp70, Hsp90, and Hsp104 families, collaborate to regulate protein aggregation.…”

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confidence: 99%

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Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

Walter

Smith

Wisén

et al. 2011

Journal of Biological Chemistry

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In Saccharomyces cerevisae, expanded polyglutamine (polyQ) fragments are assembled into discrete cytosolic aggregates in a process regulated by the molecular chaperones Hsp26, Hsp70, Hsp90, and Hsp104. To better understand how the different chaperones might cooperate during polyQ aggregation, we used sequential immunoprecipitations and mass spectrometry to identify proteins associated with either soluble (Q25) or aggregation-prone (Q103) fragments at both early and later times after induction of their expression. We found that Hsp26, Hsp70, Hsp90, and other chaperones interact with Q103, but not Q25, within the first 2 h. Further, Hsp70 and Hsp90 appear to be partially released from Q103 prior to the maturation of the aggregates and before the recruitment of Hsp104. To test the importance of this seemingly ordered process, we used a chemical probe to artificially enhance Hsp70 binding to Q103. This treatment retained both Hsp70 and Hsp90 on the polyQ fragment and, interestingly, limited subsequent exchange for Hsp26 and Hsp104, resulting in incomplete aggregation. Together, these results suggest that partial release of Hsp70 may be an essential step in the continued processing of expanded polyQ fragments in yeast.The heat shock proteins (HSPs) 3 are abundant molecular chaperones that have been shown to be important for maintaining proteostasis under both normal conditions and during times of cellular stress (1-3). Together, these factors play multiple roles in quality control, especially related to polypeptide synthesis, folding, and turnover (4 -7). Moreover, HSPs are emerging as drug targets in cancer, neurodegenerative disorders and other diseases (8, 9). Thus, there is interest in better understanding how they coordinate protein quality control decisions.The major families of HSPs are named based on their approximate kDa molecular weights, including Hsp60, Hsp70, Hsp90,

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

Walter

Smith

Wisén

et al. 2011

Journal of Biological Chemistry

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“…N-terminal phosphorylation may also have consequences for the regulation of substrate choice or the recruitment of specific cofactors. The Hsp90␣ cofactor Stip1, which is known to modulate Hsp90␣ ATPase activity (61,62), was also found to be highly phosphorylated in response to DNA damage in our analysis of the proteins recognized by the a-TQ-P antibody (supplemental Fig. S1), suggesting that PIKK activity may modify the interaction of Hsp90␣ with this cofactor.…”

Section: Discussionmentioning

confidence: 95%

Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

Quanz

Herbette²,

Sayarath³

et al. 2012

Journal of Biological Chemistry

107

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Background: DNA damage triggers a complex signaling cascade that remains incompletely understood. Results: The essential chaperone Hsp90␣ is phosphorylated by DNA damage signaling kinases and accumulates at DNA damage sites. Conclusion: Hsp90␣ is directly involved in DNA repair. Significance: Our results provide an explanation for the radiosensitizing effect of Hsp90 inhibitors and identify phosphorylated Hsp90␣ as a potential biomarker for genetic instability.

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“…Whether that is the case for yeast, human and Pf Hsp90 is not known since, to the best of our knowledge, they have not yet been measured side by side. Furthermore, the binding affinities of Hsp90 for inhibitors can be influenced by its interactions with co-chaperones [17,22,[37][38][39][40][41], which in turn may be modulated by posttranslational modifications of Hsp90 (see for example refs. [42][43][44]).…”

Section: Discussionmentioning

confidence: 99%

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider

Péli-Gulli

Briand

et al. 2009

Molecular and Biochemical Parasitology

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Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90α or Hsp90β, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window

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Independent Regulation of Hsp70 and Hsp90 Chaperones by Hsp70/Hsp90-organizing Protein Sti1 (Hop1)

Cited by 102 publications

References 38 publications

Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

Ordered Assembly of Heat Shock Proteins, Hsp26, Hsp70, Hsp90, and Hsp104, on Expanded Polyglutamine Fragments Revealed by Chemical Probes

Heat Shock Protein 90α (Hsp90α) Is Phosphorylated in Response to DNA Damage and Accumulates in Repair Foci

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

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