Molecular Fingerprinting Of Hsp27 Anti-Apoptotic Activity

Apoptosis is an evolutionarily conserved mechanism crucial to the homeostasis of cell numbers, tissue development, and immune response. Several checkpoints regulate the activation of apoptosis, including heat shock protein 27 (Hsp27), an anti‐apoptotic regulator that blocks several steps in the apoptotic cascade. However, the structural basis for this protective effect remains unknown. Increased cardiomyocyte (CM) apoptosis contributes to cardiovascular disease (CVD) in doxorubicin (dox)‐treated cancer patients. CM apoptosis requires the activation of caspase‐3, a key evolutionarily conserved protease. We showed that Hsp27 associates with and inhibits caspase‐3, but the exact mechanisms remain unknown. The goal of this study was to determine the structural‐functional relationships responsible for the anti‐apoptotic activity of Hsp27. Serial deletion clones of Hsp27 were used to fingerprint the Hsp27 domains responsible for the association with caspase‐3 and inhibition of apoptosis. We identified different molecular signatures responsible for caspase‐3 association and the regulation of cytochrome c. These findings contribute to the understanding of Hsp27 anti‐apoptotic function and will aid in the development of anti‐apoptotic peptide therapies for the prevention of CVD in cancer patients. This research was funded by AHA SURF and ASC URS to JCT and RO1 HL075040 and NSF‐MCB 0542244 to AID