Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.

Abstract	von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease.
Authors	M Ohh, C W Park, M Ivan, M A Hoffman, T Y Kim, L E Huang, N Pavletich, V Chau, W G Kaelin
Journal	Nature cell biology (Nat Cell Biol) Vol. 2 Issue 7 Pg. 423-7 (Jul 2000) ISSN: 1465-7392 [Print] England
PMID	10878807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cell Extracts DNA-Binding Proteins Elongin HIF1A protein, human Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Nuclear Proteins Proteins Transcription Factors Tumor Suppressor Proteins Ubiquitins Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein Ligases VHL protein, human Deferoxamine Oxygen
Topics	Cell Extracts DNA-Binding Proteins (metabolism) Deferoxamine (pharmacology) Elongin HeLa Cells Humans Hypoxia-Inducible Factor 1 Hypoxia-Inducible Factor 1, alpha Subunit Ligases Mutation Nuclear Proteins (metabolism) Oxygen (metabolism) Protein Binding Protein Processing, Post-Translational (drug effects) Protein Structure, Tertiary Proteins (chemistry, genetics, metabolism) Transcription Factors (metabolism) Transfection Tumor Cells, Cultured Tumor Suppressor Proteins Ubiquitin-Protein Ligases Ubiquitins (metabolism) Von Hippel-Lindau Tumor Suppressor Protein

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