Abstract
Mutation of the VHL tumor suppressor is associated with the inherited von Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible proteins. The structure of the ternary complex at 2.7 angstrom resolution shows two interfaces, one between VHL and ElonginC and another between ElonginC and ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL responsible for ElonginC binding. A mutational patch on a separate domain of VHL indicates a second macromolecular binding site. The structure extends the similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins for degradation, supporting the hypothesis that VHL may function in an analogous pathway.
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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Binding Sites
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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Cloning, Molecular
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Crystallography, X-Ray
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Elongin
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Genes, Tumor Suppressor*
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Humans
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Hydrogen Bonding
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Ligases*
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Mutation, Missense
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Neoplasms / genetics
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Protein Conformation
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Protein Folding
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Protein Structure, Secondary
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Proteins / chemistry*
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Proteins / genetics
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Proteins / metabolism
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S-Phase Kinase-Associated Proteins
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Surface Properties
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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
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von Hippel-Lindau Disease / genetics*
Substances
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Cell Cycle Proteins
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Elongin
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Proteins
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S-Phase Kinase-Associated Proteins
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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