Wisén, S and Bertelsen, EB and Thompson, AD and Patury, S and Ung, P and Chang, L and Evans, CG and Walter, GM and Wipf, P and Carlson, HA and Brodsky, JL and Zuiderweg, ERP and Gestwicki, JE
(2010)
Binding of a small molecule at a protein-protein interface regulates the chaperone activity of Hsp70-Hsp40.
ACS Chemical Biology, 5 (6).
611 - 622.
ISSN 1554-8929
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Abstract
Heat shock protein 70 (Hsp70) is a highly conserved molecular chaperone that plays multiple roles in protein homeostasis. In these various tasks, the activity of Hsp70 is shaped by interactions with co-chaperones, such as Hsp40. The Hsp40 family of co-chaperones binds to Hsp70 through a conserved J-domain, and these factors stimulate ATPase and protein-folding activity. Using chemical screens, we identified a compound, 115-7c, which acts as an artificial co-chaperone for Hsp70. Specifically, the activities of 115-7c mirrored those of a Hsp40; the compound stimulated the ATPase and protein-folding activities of a prokaryotic Hsp70 (DnaK) and partially compensated for a Hsp40 loss-of-function mutation in yeast. Consistent with these observations, NMR and mutagenesis studies indicate that the binding site for 115-7c is adjacent to a region on DnaK that is required for J-domain-mediated stimulation. Interestingly, we found that 115-7c and the Hsp40 do not compete for binding but act in concert. Using this information, we introduced additional steric bulk to 115-7c and converted it into an inhibitor. Thus, these chemical probes either promote or inhibit chaperone functions by regulating Hsp70-Hsp40 complex assembly at a native protein-protein interface. This unexpected mechanism may provide new avenues for exploring how chaperones and co-chaperones cooperate to shape protein homeostasis. © 2010 American Chemical Society.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
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Wisén, S | | | | Bertelsen, EB | | | | Thompson, AD | | | | Patury, S | | | | Ung, P | | | | Chang, L | | | | Evans, CG | | | | Walter, GM | | | | Wipf, P | pwipf@pitt.edu | PWIPF | | Carlson, HA | | | | Brodsky, JL | jbrodsky@pitt.edu | JBRODSKY | 0000-0002-6984-8486 | Zuiderweg, ERP | | | | Gestwicki, JE | | | |
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Date: |
18 June 2010 |
Date Type: |
Publication |
Journal or Publication Title: |
ACS Chemical Biology |
Volume: |
5 |
Number: |
6 |
Page Range: |
611 - 622 |
DOI or Unique Handle: |
10.1021/cb1000422 |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
1554-8929 |
MeSH Headings: |
Escherichia coli--chemistry; Escherichia coli--genetics; Escherichia coli--metabolism; Escherichia coli Proteins--chemistry; Escherichia coli Proteins--genetics; Escherichia coli Proteins--metabolism; Gene Expression Regulation, Fungal--drug effects; HSP40 Heat-Shock Proteins--metabolism; HSP70 Heat-Shock Proteins--chemistry; HSP70 Heat-Shock Proteins--genetics; HSP70 Heat-Shock Proteins--metabolism; Models, Molecular; Mutagenesis, Site-Directed; Protein Binding; Protein Structure, Tertiary; Saccharomyces cerevisiae--genetics; Saccharomyces cerevisiae--metabolism; Saccharomyces cerevisiae Proteins--genetics; Saccharomyces cerevisiae Proteins--metabolism; Small Molecule Libraries--chemistry; Small Molecule Libraries--pharmacology |
Other ID: |
NLM NIHMS240226, NLM PMC2950966 |
PubMed Central ID: |
PMC2950966 |
PubMed ID: |
20481474 |
Date Deposited: |
29 May 2013 16:32 |
Last Modified: |
13 Feb 2019 12:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/18794 |
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