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J. Biol. Chem., Vol. 282, Issue 34, 24490-24494, August 24, 2007

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Structural Basis for the Function of DCN-1 in Protein Neddylation^*

Xiaoyu Yang¹, Jie Zhou¹, Lei Sun, Zhiyi Wei, Jianying Gao, Weimin Gong, Rui-Ming Xu, Zihe Rao^¶, and Yingfang Liu²

From the National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, the Structural Biology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, New York 10016, and the ^¶Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China

Covalent modification by Nedd8 (neddylation) stimulates the ubiquitin-protein isopeptide ligase (E3) activities of Cullins. DCN-1, an evolutionarily conserved protein, promotes neddylation of Cullins in vivo, binds directly to Nedd8, and associates with Cdc53 in the budding yeast Saccharomyces cerevisiae. The 1.9Å resolution structure of yeast DCN-1 shows that the region encompassing residues 66–269 has a rectangular parallelepiped-like all -helical structures, consisting of an EF-hand motif N-terminal domain and a closely juxtaposed C-terminal domain with six -helices. The EF-hand motif structure is highly similar to that of the c-Cbl ubiquitin E3 ligase. We also demonstrate that DCN-1 directly binds to Rbx-1, a factor important for protein neddylation. The structural and biochemical results are consistent with the role of DCN-1 as a scaffold protein in a multisubunit neddylation E3 ligase complex.

Received for publication, March 6, 2007 , and in revised form, June 11, 2007.

^* This work was supported by Project `863' grant named as"Structural Study of Cancer-related Proteins."Project `973' (number 2007 CB914304). 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 atomic coordinates and structure factors (codes 2IS9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains a supplemental method and four supplemental figures.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. E-mail: liuy{at}ibp.ac.cn.