Heat shock protein A (HSPA)

Heat shock protein A (HSPA), widely known as the Heat shock protein 70 (Hsp70) family, comprises a group of highly conserved molecular chaperones that are central to maintaining cellular proteostasis [1, 16]. These proteins function as ATP-dependent enzymes that facilitate the folding of nascent polypeptides, the refolding of denatured proteins, and the stabilization of proteins against aggregation under stress [1, 13]. The family includes both constitutively expressed members like HSPA8 (Hsc70), which perform essential housekeeping duties, and stress-inducible members like HSPA1A, which are upregulated in response to heat, hypoxia, and proteotoxic stress [11, 16]. In cancer, HSPA proteins are frequently overexpressed to support the stability of mutated oncoproteins and to evade apoptosis, making them attractive targets for small molecule inhibitors like VER-155008 and JG-98 [6, 11, 12]. Conversely, in neurodegenerative diseases such as Alzheimer's and Parkinson's, HSPA function is often impaired or insufficient to prevent the accumulation of toxic protein aggregates, suggesting a role for HSPA activators in therapy [5, 14]. Despite their therapeutic potential, targeting HSPA remains difficult due to the high structural homology between family members, which can lead to off-target effects and the induction of a compensatory heat shock response [6, 11].

Other names

Heat shock protein 70Hsp7070 kDa heat shock proteinDnaKMolecular chaperone Hsp70HSPA family

HSPA modulators primarily function by inhibiting the ATPase activity of the N-terminal nucleotide-binding domain (NBD), disrupting the substrate-binding domain (SBD) interactions, or allosterically modulating the chaperone cycle. These actions prevent the proper folding of client proteins, leading to their aggregation or proteasomal degradation.