Function, Therapeutic Potential, and Inhibition of Hsp70 Chaperones

Abstract

Hsp70s are among the most highly conserved proteins in all of biology. Through an iterative binding and release of exposed hydrophobic residues on client proteins, Hsp70s can prevent aggregation and promote folding to the native state of their client proteins. The human proteome contains eight canonical Hsp70s. Because Hsp70s are relatively promiscuous they play a role in folding a large proportion of the proteome. Hsp70s are implicated in disease through their ability to regulate protein homeostasis. In recent years, researchers have attempted to develop selective inhibitors of Hsp70 isoforms to better understand the role of individual isoforms in biology and as potential therapeutics. Selective inhibitors have come from rational design, forced localization, and serendipity, but the development of completely selective inhibitors remains elusive. In the present review, we discuss the Hsp70 structure and function, the known Hsp70 client proteins, the role of Hsp70s in disease, and current efforts to discover Hsp70 modulators.

A Proteomic Analysis of Discolored Tooth Surfaces after the Use of 0.12% Chlorhexidine (CHX) Mouthwash and CHX Provided with an Anti-Discoloration System (ADS)

“…Specifically, DnaK is a bacterial chaperone protein belonging to the Hsp70 family (70 kDa heat shock protein), which is highly conserved among all species from bacteria to humans and is involved in many biological and cellular processes under both physiological and stress conditions. The system regulates the heat shock response, the refolding of newly synthesized proteins through binding to nascent polypeptide chains, the assembly and translocation across membranes, the prevention and regulation of the degradation of protein aggregates, the refolding and repair of misfolded proteins and the control of the conformational status of preexisting proteins [ 32 , 33 ]. Bacterial DnaK is a stress-inducible protein that enables cell survival under stress conditions by preventing protein denaturation upon stress [ 34 ].…”

Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT

“…The picture is further complicated by the compensatory elevation of HSP70 levels that follows the inhibition of HSP70 [ 71 ]. In turn, there are numerous reported HSP70 inhibitors, which also differ in isoform specificity and other chemical and biological traits [ 72 ]. While an early trial of an HSP70 inhibitor (MKT-077) failed due to poor bioavailability and high renal toxicity [ 73 ], there is considerable effort towards developing HSP70 inhibitors with improved pharmacological properties [ 72 ].…”

“…In turn, there are numerous reported HSP70 inhibitors, which also differ in isoform specificity and other chemical and biological traits [ 72 ]. While an early trial of an HSP70 inhibitor (MKT-077) failed due to poor bioavailability and high renal toxicity [ 73 ], there is considerable effort towards developing HSP70 inhibitors with improved pharmacological properties [ 72 ]. Distinct roles of different HSP70 isoforms and their different susceptibility to different inhibitors add to the complexity of the system, which is already complicated by the participation of the HSP70 proteins in both the general response to proteotoxicity and in specific signaling cascades.…”

Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70

“…This can occur during de novo protein synthesis at the ribosome, with aggregation prone protein intermediates, with stress-denatured proteins or during the assembly and disassembly of protein complexes. HSP70s interact with almost all newly synthesized, partially folded proteins and Molecules 2022, 27, 817 2 of 22 are able to recognize such a diverse range of proteins by interacting with short motifs of five amino acids, enriched with hydrophobic residues, which are found in practically all polypeptides [3].…”