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Binding of a small molecule at a protein-protein interface regulates the chaperone activity of Hsp70-Hsp40

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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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
Status: Published
CreatorsEmailPitt UsernameORCID
Wisén, S
Bertelsen, EB
Thompson, AD
Patury, S
Ung, P
Chang, L
Evans, CG
Walter, GM
Wipf, Ppwipf@pitt.eduPWIPF
Carlson, HA
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Zuiderweg, ERP
Gestwicki, JE
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


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