Heat shock 70 kDa protein 1A (HSP70) (HSP70)

Heat shock 70 kDa protein 1A (HSP70) is a ubiquitous molecular chaperone essential for maintaining cellular protein homeostasis by assisting in the folding of nascent polypeptides and the refolding of misfolded proteins (UniProt P0DMV8). It consists of an N-terminal nucleotide-binding domain (NBD) with ATPase activity and a C-terminal substrate-binding domain (SBD) that recognizes and binds to hydrophobic patches on misfolded or unfolded client proteins (PubMed: 29107545). In many cancers, HSP70 is overexpressed to support the stability of oncogenic client proteins and to inhibit apoptosis, making it a significant therapeutic target (PubMed: 25613110). In neurodegenerative diseases, the interaction of the HSP70 SBD with misfolded proteins like Tau or alpha-synuclein is explored to promote their clearance and prevent toxic aggregation (PubMed: 28235147). Small molecule inhibitors targeting the SBD or its allosteric communication with the NBD aim to disrupt these chaperone-client interactions, leading to the degradation of pathogenic proteins via the ubiquitin-proteasome system (PubMed: 19403813). Examples of such inhibitors include MKT-077 and Pifithrin-mu, which have shown potential in preclinical models of cancer and protein-misfolding disorders.

Other names

HSPA1AHSPA1BHSP72Heat shock 70 kDa protein 1Chaperone protein HSP70

Inhibition of the chaperone cycle by binding to the substrate-binding domain (SBD) or allosteric sites, preventing the stabilization of misfolded client proteins and promoting their degradation (PubMed: 25613110).