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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.

Original publication

DOI

10.1093/emboj/20.18.5197

Type

Journal article

Journal

EMBO J

Publication Date

17/09/2001

Volume

20

Pages

5197 - 5206

Keywords

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