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

The Heat shock protein 70–Bcl-2-associated athanogene 1M (Hsp70–BAG-1M) protein–protein interaction complex is a critical regulatory assembly in the cellular proteostasis network, comprising the molecular chaperone Heat shock protein 70 (Hsp70) and its co-chaperone Bcl-2-associated athanogene 1M (BAG-1M) (UniProt: P08107, Q99933). BAG-1M functions as a nucleotide exchange factor (NEF) that binds to the ATPase domain of Hsp70, stimulating the release of ADP and facilitating the turnover of client proteins (PMID: 11226344). This interaction plays a pivotal role in determining protein fate, linking the chaperone machinery to the ubiquitin-proteasome system to regulate whether proteins are refolded or degraded (PMID: 10675341). In many cancers, the Hsp70–BAG-1M complex is upregulated and promotes cell survival by stabilizing oncogenic signaling molecules such as Raf-1 and FoxM1 (PMID: 25564440). In neurodegenerative diseases, the complex is involved in the processing of aggregate-prone proteins like tau and alpha-synuclein (PMID: 15831476). Therapeutic strategies targeting this complex involve small-molecule inhibitors like JG-98, which allosterically disrupt the interaction to induce the degradation of pro-survival clients and trigger apoptosis in malignant cells (PMID: 25564440). However, the high conservation of Hsp70 across tissues presents significant challenges for achieving therapeutic selectivity and avoiding systemic toxicity.

Other names

Hsp70–BAG1M complexHsc70–BAG-1M complexHsp70–Rap46 complexHsp70–Hap46 complexHsp70–BAG-1 interactionHsp70–BAG-1 PPI complex

Allosteric inhibition of the protein-protein interaction between the Hsp70 nucleotide-binding domain and the BAG domain of BAG-1M, which prevents nucleotide exchange, stalls the chaperone cycle, and leads to the degradation of oncogenic client proteins.