College of Sciences
Chemistry & Biochemistry
Prostate apoptosis response-4 (Par-4) is a pro-apoptotic tumor suppressor protein. Down-regulation of this protein has been reported in a myriad of cancers. Conversely, up-regulation of Par-4 is found to be associated with several neurodegenerative disorders. Par-4 is unique in the sense it can selectively induce apoptosis in cancer cells. For this, caspase-dependent intracellular cleavage of Par-4 is essential to produce the functionally active fragment, cl-Par-4 (caspase-cleaved Par-4). The cl-Par-4 protein inhibits the NF-κB-mediated cell survival pathway and causes selective apoptosis in various tumor cells.
Our laboratory is interested in determining the structure of cl-Par-4 and understanding it’s interaction with various proteins. Currently, we are using biophysical techniques such as circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and SDS-PAGE to characterize the structure of cl-Par-4 in the presence of various concentrations of monovalent and divalent ions, in order to shed light on the possible ion-specific role of cl-Par-4 in inducing structure and self-association of this protein. Results show that effects on cl-Par-4 conformation are ion-specific, and effects of divalent cations are considerably more pronounced than effects from monovalent cations. We have also found that the cl-Par-4 shows a better stability in presence of Cl- ions than in presence of SO42- ions. Further, with the help of D313K mutant of cl-Par-4, we investigated that charge-charge repulsion between similar charged amino acid residues in leucine zipper is responsible for high salt at neutral pH or low salt at low pH requirement of cl-Par-4. All these findings will be helpful in getting the structured conformation of cl-Par-4 and, therefore, determining the structure of this protein via X-ray crystallography or via nuclear magnetic resonance (NMR).
cl-Par-4, Tumor suppressor protein, IDPs
Biochemistry | Biophysics | Molecular Biology
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Raut, Krishna; Pandey, Samjhana; Clark, Andrea M.; Ponniah, Komala; and Pascal, Steven M., "A Pathway to Solving the Structure of cl-Par-4 Tumor Suppressor Protein: Challenges & Findings" (2022). College of Sciences Posters. 4.