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Science 16 April 1999:
Vol. 284. no. 5413, pp. 455 - 461
DOI: 10.1126/science.284.5413.455
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Research Articles

Structure of the VHL-ElonginC-ElonginB Complex: Implications for VHL Tumor Suppressor Function

Charles E. Stebbins, 1 William G. Kaelin Jr., 2 Nikola P. Pavletich 3*

Mutation of the VHL tumor suppressor is associated with the inherited von Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible proteins. The structure of the ternary complex at 2.7 angstrom resolution shows two interfaces, one between VHL and ElonginC and another between ElonginC and ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL responsible for ElonginC binding. A mutational patch on a separate domain of VHL indicates a second macromolecular binding site. The structure extends the similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins for degradation, supporting the hypothesis that VHL may function in an analogous pathway.

1 Department of Biochemistry and Structural Biology, Joan and Sanford I. Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
2 Dana-Farber Cancer Institute and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
3 Cellular Biochemistry and Biophysics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
*   To whom correspondence should be addressed.

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J. Med. Genet. 39, 463-472
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Association of the P-Glycoprotein Transporter MDR1C3435T Polymorphism with the Susceptibility to Renal Epithelial Tumors.
M. Siegsmund, U. Brinkmann, E. Schaffeler, G. Weirich, M. Schwab, M. Eichelbaum, P. Fritz, O. Burk, J. Decker, P. Alken, et al. (2002)
J. Am. Soc. Nephrol. 13, 1847-1854
   Abstract »    Full Text »    PDF »
Structure of an HIF-1alpha -pVHL Complex: Hydroxyproline Recognition in Signaling.
J.-H. Min, H. Yang, M. Ivan, F. Gertler, W. G. Kaelin Jr., and N. P. Pavletich (2002)
Science 296, 1886-1889
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Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma.
M. S. Wiesener, M. Seyfarth, C. Warnecke, J. S. Jurgensen, C. Rosenberger, N. V. Morgan, E. R. Maher, U. Frei, and K.-U. Eckardt (2002)
Blood 99, 3562-3565
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Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1{alpha} Is Governed by a von Hippel-Lindau Protein-Independent, Hydroxylation-Regulated Association with p300/CBP.
N. Sang, J. Fang, V. Srinivas, I. Leshchinsky, and J. Caro (2002)
Mol. Cell. Biol. 22, 2984-2992
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Low mitochondrial respiratory chain content correlates with tumor aggressiveness in renal cell carcinoma.
H. Simonnet, N. Alazard, K. Pfeiffer, C. Gallou, C. Beroud, J. Demont, R. Bouvier, H. Schagger, and C. Godinot (2002)
Carcinogenesis 23, 759-768
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Role of the von Hippel-Lindau Tumor Suppressor Gene in the Formation of {beta}1-Integrin Fibrillar Adhesions.
M. A. Esteban-Barragan, P. Avila, M. Alvarez-Tejado, M. D. Gutierrez, A. Garcia-Pardo, F. Sanchez-Madrid, and M. O. Landazuri (2002)
Cancer Res. 62, 2929-2936
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Diverse Effects of Mutations in Exon II of the von Hippel-Lindau (VHL) Tumor Suppressor Gene on the Interaction of pVHL with the Cytosolic Chaperonin and pVHL-Dependent Ubiquitin Ligase Activity.
W. J. Hansen, M. Ohh, J. Moslehi, K. Kondo, W. G. Kaelin, and W. J. Welch (2002)
Mol. Cell. Biol. 22, 1947-1960
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Erythropoietin, tumours and the von Hippel-Lindau gene: towards identification of mechanisms and dysfunction of oxygen sensing.
M. S. Wiesener and K.-U. Eckardt (2002)
Nephrol. Dial. Transplant. 17, 356-359
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Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex.
E. Querido, P. Blanchette, Q. Yan, T. Kamura, M. Morrison, D. Boivin, W. G. Kaelin, R. C. Conaway, J. W. Conaway, and P. E. Branton (2001)
Genes & Dev. 15, 3104-3117
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The von Hippel-Lindau Tumor Suppressor Protein Mediates Ubiquitination of Activated Atypical Protein Kinase C.
H. Okuda, K. Saitoh, S.-i. Hirai, K. Iwai, Y. Takaki, M. Baba, N. Minato, S. Ohno, and T. Shuin (2001)
J. Biol. Chem. 276, 43611-43617
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The Von Hippel-Lindau Protein Interacts with Heteronuclear Ribonucleoprotein A2 and Regulates Its Expression.
P. A. Pioli and W. F. C. Rigby (2001)
J. Biol. Chem. 276, 40346-40352
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Endoplasmic Reticulum Stress Prolongs GH-Induced Janus Kinase (JAK2)/Signal Transducer and Activator of Transcription (STAT5) Signaling Pathway.
A. Flores-Morales, L. Fernandez, E. Rico-Bautista, A. Umana, C. Negrin, J.-G. Zhang, and G. Norstedt (2001)
Mol. Endocrinol. 15, 1471-1483
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Molecular Pathogenesis of the Von Hippel-Lindau Hereditary Cancer Syndrome: Implications for Oxygen Sensing.
H. Yang and W. G. Kaelin Jr. (2001)
Cell Growth Differ. 12, 447-455
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von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF.
M. A. Hoffman, M. Ohh, H. Yang, J. M. Klco, M. Ivan, and W. G. Kaelin Jr (2001)
Hum. Mol. Genet. 10, 1019-1027
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Contrasting effects on HIF-1{{alpha}} regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.
S. C. Clifford, M. E. Cockman, A. C. Smallwood, D. R. Mole, E. R. Woodward, P. H. Maxwell, P. J. Ratcliffe, and E. R. Maher (2001)
Hum. Mol. Genet. 10, 1029-1038
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VHL tumor suppressor regulates Cl-/HCO3- exchange and Na+/H+ exchange activities in renal carcinoma cells.
S. A. KARUMANCHI, L. JIANG, B. KNEBELMANN, A. K. STUART-TILLEY, S. L. ALPER, and V. P. SUKHATME (2001)
Physiol Genomics 5, 119-128
   Abstract »    Full Text »    PDF »


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