TY  - JOUR
ID  - pittir18794
UR  - http://d-scholarship-dev.library.pitt.edu/18794/
IS  - 6
A1  - Wisén, S
A1  - Bertelsen, EB
A1  - Thompson, AD
A1  - Patury, S
A1  - Ung, P
A1  - Chang, L
A1  - Evans, CG
A1  - Walter, GM
A1  - Wipf, P
A1  - Carlson, HA
A1  - Brodsky, JL
A1  - Zuiderweg, ERP
A1  - Gestwicki, JE
Y1  - 2010/06/18/
N2  - 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.
JF  - ACS Chemical Biology
VL  - 5
SN  - 1554-8929
TI  - Binding of a small molecule at a protein-protein interface regulates the chaperone activity of Hsp70-Hsp40
SP  - 611 
AV  - public
EP  -  622
ER  -