The Caspase-Cleaved Par-4 Tumor Suppressor Folds at Acidic pH
College of Sciences
The prostate apoptosis response-4 (Par-4) tumor suppressor selectrively kills cancer cells via apoptosis but leaves healthy cells unharmed. Full length Par-4 is 38 kilodaltons and is predominantly intrinsically disordered in vitro. As an intrinsically disordered protein (IDP), Par-4 is flexible and can acquire different conformations based on environment. Par-4 is cleaned at D131 by caspase-3 which generates the 25 kilodalton fragment (cl-Par-3). CL-Par-4 is the activated fragment that enters the nucleus and inhibits TOPO-1, Bcl-2, and NF-KB that function in cancer cell pro-survival pathways. Cl-Par-4 has a selective for apoptosis induction in cancer cells (SAC) domain with a nuclear localization signal (NLS2) and a C-terminal coiled coil domain with a leucine zipper. Many apoptotic interactions involving Par-3 are mediated via the coiled coil and leucine zipper. Here, the structure of cl-Par-4 was investigated using circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding cl-Par-4 where aggregation occurs at neutral pH, but a largely folded confirmation is present at acidic pH. This is the first evidence of structure outside of the coiled coil domain reported in the Par-4 tumor suppressor. These results have implications for understanding both cl_ar-4 structure and function in relation to cellular localization.
Clark, Andrea; Ponniah, Komala; Warden, Meghan; Raitt, Emily; Yawn, Andrea; and Pascal, Stephen, "The Caspase-Cleaved Par-4 Tumor Suppressor Folds at Acidic pH" (2019). College of Sciences Posters. 5.