Heat shock 70 kDa protein–Bcl-2-associated athanogene 1 protein-protein interaction (Hsp70–BAG-1 PPI)

The interaction between Heat shock 70 kDa protein (Hsp70) and Bcl-2-associated athanogene 1 (BAG-1) is a critical regulatory node in the cellular protein folding machinery (UniProt: P0DMV8, Q99933). Hsp70 is a molecular chaperone that assists in protein folding and prevents aggregation, while BAG-1 acts as a nucleotide exchange factor (NEF) that binds to the Hsp70 nucleotide-binding domain (NBD) (PubMed: 10551805). This interaction stimulates the release of ADP from Hsp70, facilitating the binding of ATP and the subsequent release of client proteins to complete the chaperone cycle (PubMed: 11248689). In many cancers, both Hsp70 and BAG-1 are overexpressed, leading to the stabilization of oncogenic proteins such as Akt, Raf-1, and various steroid receptors, which promote cell survival and proliferation (PubMed: 15671246). Consequently, the Hsp70–BAG-1 protein-protein interaction (PPI) has emerged as a promising therapeutic target for inducing proteotoxicity in malignant cells (PubMed: 23934152). Small molecule inhibitors, such as the allosteric inhibitor JG-98 and Thioflavin S derivatives, have been developed to disrupt this interface, leading to the degradation of client proteins and the induction of apoptosis (PubMed: 25852015).

Other names

Hsp70–BAG1 interactionHsp70–BAG-1M complexHSPA1A–BAG1 interactionHsp70–BAG-1M protein-protein interaction

Inhibition of the protein-protein interaction between the Hsp70 nucleotide-binding domain and the BAG domain of BAG-1, preventing nucleotide exchange and disrupting the chaperone-mediated stabilization of oncogenic client proteins (PubMed: 23934152).