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A Molecular Basis for Stabilization of the von Hippel-Lindau (VHL) Tumor Suppressor Protein by Components of the VHL Ubiquitin Ligase

Kamura, Takumi and Brower, Christopher S. and Conaway, Ronald C. and Conaway, Joan W. (2002) A Molecular Basis for Stabilization of the von Hippel-Lindau (VHL) Tumor Suppressor Protein by Components of the VHL Ubiquitin Ligase. Journal of Biological Chemistry, 277 (33). pp. 30388-30393. ISSN 0021-9258.

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The multiprotein von Hippel-Lindau (VHL) tumor suppressor (CBCVHL, Cul2-Elongin BC-VHL) and SCF (Skp1-Cul1/Cdc53-F-box protein) complexes are members of structurally related families of E3 ubiquitin ligases that use a heterodimeric module composed of a member of the Cullin protein family and the RING finger protein Rbx1 (ROC1/Hrt1) to activate ubiquitylation of target proteins by the E2 ubiquitin-conjugating enzymes Ubc5 and Cdc34. VHL and F-box proteins function as the substrate recruitment subunits of CBCVHL and SCF complexes, respectively. In cells, many F-box proteins are short lived and are proposed to be ubiquitylated by an autocatalytic mechanism and destroyed by the proteasome following assembly into SCF complexes. In contrast, the VHL protein is stabilized by interaction with the Elongin B and C subunits of CBCVHL in cells. In this report, we have presented direct biochemical evidence that unlike the F-box protein Cdc4, which is ubiquitylated in vitro by Cdc34 in the context of the SCF, the VHL protein is protected from Ubc5-catalyzed ubiquitylation following assembly into the CBCVHL complex. CBCVHL is continuously required for negative regulation of hypoxia-inducible transcription factors in normoxic cells and of SCF complexes, many of which function only transiently during the cell cycle or in response to cellular signals. Our findings provide a molecular basis for the different modes of cellular regulation of VHL and F-box proteins and are consistent with the known roles of CBCVHL.

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Additional Information:Copyright © 2002 by the American Society for Biochemistry and Molecular Biology. Received for publication, April 8, 2002, and in revised form, June 4, 2002. Published, JBC Papers in Press, June 4, 2002, DOI 10.1074/jbc.M203344200 We thank A. Weissman (National Institutes of Health) for cDNA encoding hUbc5a, J. W. Harper and S. Elledge (Baylor) for baculoviruses encoding Cdc53 and Skp1, and F. Barnett for help with preparation of the figures. This work was supported in part by National Institutes of Health Grant R37 GM41628. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Issue or Number:33
Record Number:CaltechAUTHORS:KAMjbc02
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3488
Deposited By: Archive Administrator
Deposited On:08 Jun 2006
Last Modified:02 Oct 2019 23:03

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