Binding of natively unfolded HIF-1α ODD domain to p53

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a crucial role in mediating oxygen response in the cell. Using biophysical techniques, we characterized two fragments of the HIF-1alpha subunit, one the full-length ODD domain (residues 403-603) and the second comprising the N-TAD (N-transactivation domain) and inhibitory domain (residues 530-698). Both were unstructured in solution under physiological conditions and so belong to the family of natively unfolded proteins. The HIF-1alpha ODD domain binds weakly to the isolated p53 core domain but tightly to full-length p53 to give a complex of one HIF-1alpha ODD domain with a p53 dimer. By being unstructured, the HIF-1alpha ODD domain can thread both its binding sites through the p53 multimer and bind tightly by the "chelate effect." These results support the idea that hypoxic p53-mediated apoptosis does involve the direct binding of HIF-1alpha to p53.