Autoinhibition of untimely DNA binding by structural disorder in the full-length peroxisome proliferator-activated receptors (PPARs)

Structural disorder in nuclear receptors is essential for gene transcription, but mechanisms are lacking. Using experiment and computation, including residue-resolution NMR, we demonstrate how structural disorder in full-length peroxisome proliferator-activated receptors (PPARs) contributes to function. We show that the disordered AB domain of PPARγ and PPARα interact dominantly and dynamically with the DNA binding domain (DBD) via two regions that, when tested in cells, constitute active transactivation domains. For PPARγ, we provide an integrative structural model of the full-length protein, and show that upon DNA binding to the DBD, but not by ligand binding to the LBD, the AB domains are released to an open, accessible state. We demonstrate that the interactions between the AB domain and the DBD lead to autoinhibition affecting DNA binding affinity negatively with little effect on DNA binding specificity. We show that autoinhibition is also present in the heterodimer with RXRα, but is less pronounced due to higher DNA binding affinity. Thus, our work suggests a role for the disordered AB domain in preventing untimely DNA binding to the PPAR monomers. Interdomain interactions by the disordered N-terminal region in PPAR transcription factors lead to autoinhibition of DNA binding. The effect is strongest for the monomer suggesting inhibition of untimely DNA binding prior to heterodimer formation.