QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 18, Issue 3, 899-909, March 2007

This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: E06-06-0542v1 18/3/899    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wimuttisuk, W. Articles by Singer, J. D. Search for Related Content PubMed PubMed Citation Articles by Wimuttisuk, W. Articles by Singer, J. D.

The Cullin3 Ubiquitin Ligase Functions as a Nedd8-bound Heterodimer

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

Submitted June 21, 2006; Revised December 7, 2006; Accepted December 19, 2006
Monitoring Editor: Mark Solomon

Cullins are members of a family of scaffold proteins that assemble multisubunit ubiquitin ligase complexes to confer substrate specificity for the ubiquitination pathway. Cullin3 (Cul3) forms a catalytically inactive BTB-Cul3-Rbx1 (BCR) ubiquitin ligase, which becomes functional upon covalent attachment of the ubiquitin homologue neural-precursor-cell-expressed and developmentally down regulated 8 (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 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

This article has been cited by other articles:

				A. Y. Kim, C. C. Bommelje, B. E. Lee, Y. Yonekawa, L. Choi, L. G. Morris, G. Huang, A. Kaufman, R. J. H. Ryan, B. Hao, et al. SCCRO (DCUN1D1) Is an Essential Component of the E3 Complex for Neddylation J. Biol. Chem., November 28, 2008; 283(48): 33211 - 33220. [Abstract] [Full Text] [PDF]

				S. Maezawa, T. Hayano, K. Koiwai, R. Fukushima, K. Kouda, T. Kubota, and O. Koiwai Bood POZ containing gene type 2 is a human counterpart of yeast Btb3p and promotes the degradation of terminal deoxynucleotidyltransferase. Genes Cells, May 1, 2008; 13(5): 439 - 457. [Abstract] [Full Text] [PDF]