Apoptosis induction by the prostate apoptosis response-4 (Par-4) tumor suppressor is highly specific to cancer cells. Many medically relevant proteins such as tumor suppressors are classified as intrinsically disordered, meaning they lack stable three-dimensional structure. In vitro experiments have shown that full length Par-4 is highly disordered in physiological conditions. An important post-translational modification is cleavage of full length Par-4 at D131 by caspase-3. This generates a 24 kilodalton C-terminal fragment (cl-Par-4) that is capable of nuclear translocation. Inside the nucleus, cl-Par-4 inhibits pro-survival genes, ultimately preventing cancer cell proliferation. Previous experiments have shown that cl-Par-4 is also highly disordered in physiological conditions. Disordered proteins often gain structure in conditions such as acidic or basic pH, high salt concentration, or interactions with other proteins. We have previously shown that cl-Par-4 folds into a highly helical structure in an acidic environment. Here, we have investigated the dependence of cl-Par-4 structure on ionic strength. Biophysical techniques used include circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), intrinsic tyrosine fluorescence, and size exclusion chromatography with multi-angle light scattering (SEC-MALS). In low ionic strength conditions, cl-Par-4 aggregates and is disordered. In contrast, at high ionic strength of 1 M NaCl, cl-Par-4 forms helical tetramers. Homology modeling suggests that the tetramer may be an anti-parallel dimer of parallel dimers. This is the first evidence of a tetramer state for the Par-4 tumor suppressor, which may represent the active state conformation.<br/>

Tetramerization of the caspase-activated Par-4 tumor suppressor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.