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J. Biol. Chem., Vol. 283, Issue 48, 33211-33220, November 28, 2008

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SCCRO (DCUN1D1) Is an Essential Component of the E3 Complex for Neddylation^*

Alexander Y. Kim¹, Claire C. Bommeljé¹, Benjamin E. Lee¹, Yoshihiro Yonekawa, Lydia Choi, Luc G. Morris, Guochang Huang, Andrew Kaufman, Russel J. H. Ryan, Bing Hao^¶, Y. Ramanathan², and Bhuvanesh Singh³

From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, 10065, Department of Otolaryngology, Erasmus MC, 3015CE Rotterdam, The Netherlands, and ^¶Department of Molecular, Microbial, and Structural Biology, University of Connecticut Health Center, Farmington, Connecticut 06030

Covalent modification of cullins by the ubiquitin-like protein NEDD8 (neddylation) regulates protein ubiquitination by promoting the assembly of cullin-RING ligase E3 complexes. Like ubiquitination, neddylation results from an enzymatic cascade involving the sequential activity of a dedicated E1 (APPBP1/Uba3), E2 (Ubc12), and an ill-defined E3. We show that SCCRO (also known as DCUN1D1) binds to the components of the neddylation pathway (Cullin-ROC1, Ubc12, and CAND1) and augments but is not required for cullin neddylation in reactions using purified recombinant proteins. We also show that SCCRO recruits Ubc12NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation in purified protein assays. In contrast to findings in cellular systems where no binding is seen, we show that SCCRO and CAND1 can bind to the neddylated Cul1-ROC1 complex in assays using purified recombinant proteins. Although neddylated (not unneddylated) Cul1-ROC1 is released from CAND1 upon incubation with testis lysate from SCCRO^+/+ mice, the addition of recombinant SCCRO is required to achieve the same results in lysate from SCCRO^–/– mice. Combined, these results suggest that SCCRO is an important component of the neddylation E3 complex that functions to recruit charged E2 and is involved in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity.

Received for publication, June 10, 2008 , and in revised form, September 24, 2008.

^* This work was supported in part a George H. A. Clowes Memorial Research Career Development Award from the American College of Surgeons (to B. S.), a Clinical Innovator Award from Flight Attendant Medical Research Institute (to B. S. and Y. R.), the T. J. Martel Fund (to B. S. and V. Rusch), the Falcone Fund (to B. S. and J. Shah), an National Institutes of Health training grant (to L. C.), and a Matheson Fellowship (to Y. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Memorial Sloan-Kettering Cancer Center, Laboratory of Epithelial Cancer Biology, 1275 York Ave., New York, NY 10065. Fax: 212-717-3302; E-mail: ramanaty{at}mskcc.org. ³ To whom correspondence may be addressed: Memorial Sloan-Kettering Cancer Center, Laboratory of Epithelial Cancer Biology, 1275 York Ave., New York, NY 10065. Fax: 212-717-3302; E-mail: singhb{at}mskcc.org.

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