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Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation.

Oxygen-dependent proteolytic destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits plays a central role in regulating transcriptional responses to hypoxia. Recent studies have defined a key function for the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase (VHLE3) in this process, and have defined an interaction with HIF-1 alpha that is regulated by prolyl hydroxylation. Here we show that two independent regions within the HIF-alpha oxygen-dependent degradation domain (ODDD) are targeted for ubiquitylation by VHLE3 in a manner dependent upon prolyl hydroxylation. In a series of in vitro and in vivo assays, we demonstrate the independent and non-redundant operation of each site in regulation of the HIF system. Both sites contain a common core motif, but differ both in overall sequence and in the conditions under which they bind to the VHLE3 ligase complex. The definition of two independent destruction domains implicates a more complex system of pVHL-HIF-alpha interactions, but reinforces the role of prolyl hydroxylation as an oxygen-dependent destruction signal.

Pubmed ID: 11566883


  • Masson N
  • Willam C
  • Maxwell PH
  • Pugh CW
  • Ratcliffe PJ


The EMBO journal

Publication Data

September 17, 2001

Associated Grants


Mesh Terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cattle
  • Cell Extracts
  • Conserved Sequence
  • Cytoplasm
  • DNA-Binding Proteins
  • Hydroxylation
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ligases
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins
  • Proline
  • Protein Structure, Tertiary
  • Proteins
  • Sequence Homology, Amino Acid
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Ubiquitins
  • Von Hippel-Lindau Tumor Suppressor Protein