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

The EMBO journal | Sep 17, 2001

http://www.ncbi.nlm.nih.gov/pubmed/11566883

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 RIS Download

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