The PAAD domain OF IFI16 reveals a novel ssDNA binding function for the death domain super family

The PAAD Death domain, involved in apoptosis and inflammation, shares a 6-helix bundle fold similar to other apoptotic sub-family members (DD/DED/CARD), but with a disordered region in helix 3. To investigate the structural basis for this difference I measured and compared thermodynamic folding parameters between PAAD and CARD members and show that PAAD domains have low stability and can undergo conformational changes when induced by mutagenesis or secondary structure promoting agents. The structural plasticity of the PAAD domain is consistent with an induced fit mechanism of ligand binding that may confer different protein-ligand interactions, contrasting with the common assumption that the Death domain is a protein-protein interaction domain. Finally, I challenged the above assumption by showing that the PAAD domain from the HIN-200 family member, IFI16, has all the characteristics of a single stranded nucleic acid binding protein, motivating further studies for the discovery of new PAAD-ligand interactions and functions.