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

doi:10.1038/35017054

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

Department of Cellular and Molecular Physiology

Research output: Contribution to journal › Article › peer-review

1289 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 language	English (US)
Pages (from-to)	423-427
Number of pages	5
Journal	Nature Cell Biology
Volume	2
Issue number	7
DOIs	https://doi.org/10.1038/35017054
State	Published - 2000

All Science Journal Classification (ASJC) codes

Cell Biology

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title = "Ubiquitination of hypoxia-inducible factor requires direct binding to the β-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 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.",

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

note = "Funding Information: ACKNOWLEDGEMENTS We thank C. Stebbins for purified pVHL/elongin C/elongin B complexes and H. Franklin Bunn and M. Meyerson for critical reading of the manuscript. This work was supported by grants from the NIH and from the Murray Foundation. M.O. is a Fellow of the National Cancer Institute of Canada. W.G.K. is a Howard Hughes Medical Institute assistant investigator. Correspondence and requests for materials should be addressed to W.G.K.",

year = "2000",

doi = "10.1038/35017054",

language = "English (US)",

volume = "2",

pages = "423--427",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "Nature Publishing Group",

number = "7",

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T1 - Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel - Lindau protein

AU - Ohh, Michael

AU - Park, Cheol Won

AU - Ivan, Mircea

AU - Hoffman, Michael A.

AU - Kim, Tae You

AU - Huang, L. Eric

AU - Pavletich, Nikola

AU - Chau, Vincent

AU - Kaelin, William G.

N1 - Funding Information: ACKNOWLEDGEMENTS We thank C. Stebbins for purified pVHL/elongin C/elongin B complexes and H. Franklin Bunn and M. Meyerson for critical reading of the manuscript. This work was supported by grants from the NIH and from the Murray Foundation. M.O. is a Fellow of the National Cancer Institute of Canada. W.G.K. is a Howard Hughes Medical Institute assistant investigator. Correspondence and requests for materials should be addressed to W.G.K.

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

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JF - Nature Cell Biology

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

Abstract

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