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

Michael Ohh, Cheol Won Park, Mircea Ivan, Michael A. Hoffman, Tae You Kim, L. Eric Huang, Nikola Pavletich, Vincent Chau, William G. Kaelin

Research output: Contribution to journalArticlepeer-review

1148 Scopus citations

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 β-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an α-domain-dependent manner. This is the first function to be ascribed to the pVHL β-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.

Original languageEnglish (US)
Pages (from-to)423-427
Number of pages5
JournalNature Cell Biology
Volume2
Issue number7
DOIs
StatePublished - Oct 30 2000

All Science Journal Classification (ASJC) codes

  • Cell Biology

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