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.
