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Originally published In Press as doi:10.1074/jbc.M008295200 on October 9, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1407-1416, January 12, 2001
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Role of Exon 2-encoded beta -Domain of the von Hippel-Lindau Tumor Suppressor Protein*

Marie-Eve Bonicalzi, Isabelle Groulx, Natalie de Paulsen, and Stephen LeeDagger

From the Department of Cellular and Molecular Medicine and Kidney Research Center, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Sporadic clear cell renal carcinomas frequently harbor inactivating mutations in exon 2 of the von Hippel-Lindau (VHL) tumor suppressor gene. Here, we examine the effect of the loss of exon 2-encoded beta -domain function on VHL biochemical properties. Exon 2-encoded residues are required for VHL-mediated NEDD8 conjugation on cullin-2 and assembly with hypoxia-inducible factor alpha  (HIFalpha ) and fibronectin. These residues are not essential for VHL ability to assemble with elongin BC/cullin-2, to display E3 ubiquitin ligase activity in vitro and to confer energy-dependent nuclear import properties to a reporter protein. Localization studies in HIF-1alpha -null embryonic cells suggest that exon 2-encoded beta -domain mediates transcription-dependent nuclear/cytoplasmic shuttling of VHL independently of assembly with HIF-1alpha and oxygen concentration. Exon 3-encoded alpha -helical domain is required for VHL complex formation with BC/cullin-2 and E3 ubiquitin ligase activity, for binding to HIFalpha /fibronectin, but this domain is not essential for transcription-dependent nuclear/cytoplasmic trafficking. VHL-/- renal carcinoma cells expressing beta -domain mutants failed to produce an extracellular fibronectin matrix and to degrade HIFalpha , which accumulated exclusively in the nucleus of normoxic cells. These results demonstrate that exon 2-encoded residues are involved in two independent functions: substrate protein recognition and transcription-dependent nuclear/cytoplasmic trafficking. They also suggest that beta -domain mutations inactivate VHL function differently than alpha -domain mutations, potentially providing an explanation for the relationship between different mutations of the VHL gene and clinical outcome.

* This work was supported by an Operating Grant from the Medical Research Council of Canada (MRC) (to S. L.).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.

Dagger Scholar of the MRC. To whom correspondence should be addressed: Dept. of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada. Tel.: 613-562-5800 (ext. 8385); Fax: 613-562-5636; E-mail: slee@uottawa.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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