The Therapeutic Potential of Targeting Hsp90-Cdc37 Interactions in Several Diseases.

Heat shock protein (Hsp) 90 is an ATP-dependent chaperone and plays a vital role in the folding, maturation, and stability of a protein. Hsp90 and its client proteins have become targets of various diseases through the regulation of disease-related proteins. Inhibition of Hsp90 production and activity prevents ATP hydrolysis, resulting in the ubiquitination and proteasome degradation of client proteins. However, the Hsp90 inhibitor has obvious toxic side effects and the inevitable heat shock response. Cell division cycle 37 (Cdc37) is a crucial Hsp90 kinase-specific co-chaperone, which forms a complex with Hsp90 to regulate kinase and non-kinase client's activities, cell communication, and signal transduction. The Hsp90-Cdc37 complex maintains cell survival by stabilizing abnormal client proteins and regulating cell growth signals. The abnormal activation of Hsp90-Cdc37 protein-protein interaction (PPI) often leads to the aggravation of diseases, such as cancer and neurodegenerative diseases. Compared with ATP competitive Hsp90 inhibitors, blocking Hsp90-Cdc37 PPI has higher selectivity, fewer toxic side effects, and better application prospects. This review detailed the biological characteristics of Hsp90-Cdc37 PPI and its role in several human diseases. Besides, the latest research progress in inhibitors is summarized and discussed to guide further research and clinical application.

New insights into the mechanism of Keap1-Nrf2 interaction based on cancer-associated mutations.

AIMS: Keap1-Nrf2 signaling pathway is one of the most important antioxidant signaling pathways, and its abnormal activation is related to cancer metastasis and drug resistance. Many studies have shown Keap1 and Nrf2 mutations are closely associated with cancer occurrence. However, few studies focus on Keap1-Nrf2 binding characteristics of cancer-associated mutations. The study investigated the molecular mechanism between Keap1/Nrf2 mutations and cancer. MAIN METHODS: We have determined the crystal structure of the Keap1-Kelch domain with Nrf2 25-mer peptide. What's more, we clarified the molecular effects of Nrf2Thr80 and Nrf2Pro85 on the binding of Keap1 by the method isothermal titration calorimetry (ITC), differential scanning fluorimetry (DSF) and electrophoretic mobility shift assay (EMSA). Especially, we confirmed the effect of Thr80 and Pro85 mutations on Keap1/Nrf2 signaling pathway in HEK293T cells by RT-PCR and western blot (WB). Finally, we verified the effect of six cancer-related high-frequency somatic mutations Keap1G364C, Keap1D422N, Keap1R470C, Keap1G480W, Keap1E493Q and Keap1R601L on binding with Nrf2 through ITC experiments. KEY FINDINGS: Nrf2Thr80 and Nrf2Pro85 play a vital role in the Keap1-Nrf2 interaction. Mutant or modification at position Thr80 will disrupt the interaction. Especially, Nrf2Thr80 and Nrf2Pro85 mutations activate the expression of cytoprotective genes in HEK293T cells. As for Keap1, except G364C, the binding affinity of other cancer-related mutants to Nrf2 hardly changed, which means that Keap1 mutants can activate Nrf2 without disrupting the binding to Nrf2. SIGNIFICANCE: The study provides new insight into Keap1/Nrf2 signaling pathway and cancer.