Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Crystallography, X-Ray
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Elongin
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Humans
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Hydrogen Bonding
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Hydrophobic and Hydrophilic Interactions
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Hydroxylation
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Hydroxyproline / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit
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Ligases / chemistry*
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Ligases / genetics
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Ligases / metabolism
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Macromolecular Substances
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Mice
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Protein Conformation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Signal Transduction
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Transcription Factors / chemistry*
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Transcription Factors / metabolism
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Tumor Suppressor Proteins*
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Ubiquitin-Protein Ligases*
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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Elongin
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Macromolecular Substances
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Ligases
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VHL protein, human
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Hydroxyproline