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

Mol Cell. 2005 Jan 7;17(1):11-21. doi: 10.1016/j.molcel.2004.11.019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Base Sequence
  • Binding Sites
  • Circular Dichroism
  • DNA / genetics
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • In Vitro Techniques
  • Kinetics
  • Multiprotein Complexes
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Osmolar Concentration
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / chemistry*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Multiprotein Complexes
  • Nuclear Proteins
  • Peptide Fragments
  • Recombinant Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • DNA