Heat shock 70 kDa protein 9-Tumor protein p53 protein-protein interaction interface (Mortalin-p53 PPI) (Mortalin-p53 PPI)

The Heat shock 70 kDa protein 9-Tumor protein p53 protein-protein interaction interface is a critical regulatory site where the mitochondrial chaperone Mortalin (HSPA9) binds to the tumor suppressor protein p53. In many cancer cells, Mortalin is overexpressed and sequesters p53 in the cytoplasm, preventing its translocation to the nucleus and thereby inhibiting its ability to induce apoptosis or cell cycle arrest (Wadhwa et al., 1998, PubMed: 9694799). This interaction effectively inactivates the p53 pathway even in cells where the TP53 gene is wild-type. Therapeutic strategies targeting this interface aim to disrupt the complex using small molecules or natural compounds, such as Mortaparib or Withaferin A, thereby restoring p53's transcriptional activity and promoting cancer cell death (Wadhwa et al., 2002, PubMed: 12140244; Elakehal et al., 2020, PubMed: 32824534). While promising, targeting this interface presents challenges, including the need for high specificity to avoid disrupting Mortalin's essential roles in mitochondrial protein import and general proteostasis (UniProt: P38646). Early inhibitors like MKT-077 demonstrated proof-of-concept but were limited by systemic toxicities, leading to the development of more refined molecules like Mortaparib.

Other names

HSPA9-TP53 interactionGRP75-p53 complexPBP74-p53 interactionMortalin-p53 binding interfaceMitochondrial heat shock protein 70-p53 interaction

Disruption of the physical association between Mortalin (HSPA9) and p53, which prevents the cytoplasmic sequestration of p53 and allows its translocation to the nucleus to activate tumor-suppressive gene expression.