Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling.

The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of ...
a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, Humans, Hydrogen Bonding, Hydrophobicity, Hydroxylation, Hydroxyproline, Hypoxia-Inducible Factor 1, alpha Subunit, Ligases, Macromolecular Substances, Mice, Models, Molecular, Molecular Sequence Data, Mutation, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Signal Transduction, Transcription Factors, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Science
Date: Jun. 07, 2002
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