Heat shock 70 kDa protein (Hsp70)

Heat shock 70 kDa protein (Hsp70) is a highly conserved molecular chaperone that plays a fundamental role in cellular proteostasis by assisting in protein folding, refolding of denatured proteins, and the assembly of multi-protein complexes (UniProt P0DMV8; Murphy, 2013). It functions via an ATP-dependent mechanism where the hydrolysis of ATP in its nucleotide-binding domain (NBD) regulates the affinity of its substrate-binding domain (SBD) for client polypeptides (UniProt P0DMV8). In the context of disease, Hsp70 is often significantly upregulated in various cancers, where it acts as a survival factor by inhibiting both intrinsic and extrinsic apoptotic pathways and stabilizing oncogenic client proteins (Murphy, 2013; Kumar et al., 2016). In contrast, its role in neurodegenerative diseases is primarily protective, as it helps to prevent or dissolve the toxic protein aggregates characteristic of Alzheimer's and Parkinson's diseases (Evans et al., 2010). Pharmacological intervention typically involves small-molecule inhibitors that target the NBD or SBD to disrupt the chaperone cycle, thereby promoting the degradation of survival-related proteins in cancer cells (Kumar et al., 2016; Assimon et al., 2013). However, the high degree of homology between inducible Hsp70 and constitutive Hsc70 presents a significant challenge for achieving therapeutic selectivity (Assimon et al., 2013).

Other names

HSP70HSPA1AHSPA1BHSP72Heat shock 70 kDa protein 1HSPA1Hsp70-1Hsp70-2

Inhibition of the ATPase activity in the nucleotide-binding domain (NBD) or allosteric modulation of the substrate-binding domain (SBD) to prevent chaperone-mediated protein stabilization and induce proteotoxic stress or apoptosis (Kumar et al., 2016, PMID: 27515263; Assimon et al., 2013, PMID: 23432672).