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MBC in Press, published online ahead of print December 27, 2006
Mol. Biol. Cell 10.1091/mbc.E06-06-0542

A more recent version of this article appeared on March 1, 2007
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Submitted on June 21, 2006
Revised on December 7, 2006
Accepted on December 19, 2006

The Cullin3 Ubiquitin Ligase Functions as a Nedd8-bound Heterodimer

Wananit Wimuttisuk and Jeffrey D. Singer

The Department of Molecular Biology, Cell Biology, and Biochemistry and the Center for Genomics and Proteomics, Brown University, Providence, RI 02903

Monitoring Editor: Mark Solomon

Cullins are members of a family of scaffold proteins that assemble multi-subunit ubiquitin ligase complexes to confer substrate specificity for the ubiquitination pathway. Cullin3 (Cul3) forms a catalytically inactive BCR (BTB-Cul3-Rbx1) ubiquitin ligase, which becomes functional upon covalent attachment of the ubiquitin homologue Nedd8 near the C-terminus of Cul3. Current models suggest that Nedd8 activates cullin complexes by providing a recognition site for a ubiquitin-conjugating enzyme. Based on the following evidence, we propose that Nedd8 activates the BCR ubiquitin ligase by mediating the dimerization of Cul3. First, Cul3 is found as a neddylated heterodimer bound to a BTB domain-containing protein in vivo. Second, the formation of a Cul3 heterodimer is mediated by a Nedd8 molecule, which covalently attaches itself to one Cul3 molecule and binds to the winged-helix B (WH-B) domain at the C-terminus of the second Cul3 molecule. Third, complementation experiments revealed that coexpression of two distinct nonfunctional Cul3 mutants can rescue the ubiquitin ligase function of the BCR complex. Likewise, a substrate of the BCR complex binds heterodimeric Cul3, suggesting that the Cul3 complex is active as a dimer. These findings not only provide insight into the architecture of the active BCR complex, but also suggest assembly as a regulatory mechanism for activation of all cullin-based ubiquitin ligases.

Address correspondence to: Jeffrey D. Singer (jeffrey_singer{at}brown.edu)




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