Two sequence motifs from HIF-1α bind to the DNA-binding site of p53

Lars O. Hansson, Assaf Friedler, Stefan Freund, Stefan Rüdiger, Alan R. Fersht*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


There is evidence that hypoxia-inducible factor-1α (HIF-1α) interacts with the tumor suppressor p53. To characterize the putative interaction, we mapped the binding of the core domain of p53 (p53c) to an array of immobilized HIF-1α-derived peptides and found two peptide-sequence motifs that bound to p53c with micromolar affinity in solution. One sequence was adjacent to and the other coincided with the two proline residues of the oxygen-dependent degradation domain (P402 and P564) that act as switches for the oxygen-dependent regulation of HIF-1α. The binding affinity was independent of the hydroxylation state of P564. We found from NMR spectroscopy that these sequence motifs bind to the DNA-binding site of p53c. Because the two sequences are homologous and separated by 120 residues, and one is in a largely unstructured transactivation domain, we speculate that each sequence motif in HIF-1α binds to a different subunit of the p53 tetramer, leading to very tight binding. The binding data support the proposal that p53 provides a route for the degradation in hypoxic tumor cells of HIF-1α that is not hydroxylated at the two proline residues.

Original languageAmerican English
Pages (from-to)10305-10309
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number16
StatePublished - Aug 2002
Externally publishedYes


  • Array
  • Hypoxia
  • NMR
  • Peptide
  • VHL


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