Abstract
The molecular chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and with their "client" proteins. Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation. The core chaperones, such as the heat shock proteins Hsp60, Hsp70, and Hsp90, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This possibility suggests that these PPIs, and perhaps not the individual chaperones themselves, could be compelling drug targets. Indeed, recent efforts have yielded small molecules that inhibit (or promote) a subset of inter-chaperone PPIs. These chemical probes are being used to study chaperone networks in a range of models, and the successes with these approaches have inspired a community-wide objective to produce inhibitors for a broader set of targets. In this Review, we discuss progress toward that goal and point out some of the challenges ahead.
Highlights
Molecular chaperones help ensure protein homeostasis, playing essential roles in the folding, trafficking, sequestration, and turnover of proteins [1]
Our knowledge of Hsp90 biology has benefitted from the availability of chemical inhibitors, which can be applied to cells or organisms to ask how Hsp90 might be involved in a process
In this Review, we briefly introduce how chemical probes are developed and outline how these ideas are being applied to chaperones
Summary
They engage in widespread protein– protein interactions (PPIs) with each other and with their “client” proteins Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation. These PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation The core chaperones, such as the heat shock proteins Hsp, Hsp, and Hsp, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This is the eighth article in the JBC Reviews series “Molecular chaperones and protein quality control.”. In this Review, we briefly introduce how chemical probes are developed and outline how these ideas are being applied to chaperones
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