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J. Biol. Chem., Vol. 281, Issue 49, 38061-38070, December 8, 2006

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Amino-terminal Dimerization, NRDP1-Rhodanese Interaction, and Inhibited Catalytic Domain Conformation of the Ubiquitin-specific Protease 8 (USP8)^*

George V. Avvakumov, John R. Walker, Sheng Xue, Patrick J. Finerty, Jr., Farrell Mackenzie, Elena M. Newman, and Sirano Dhe-Paganon¹

From the Structural Genomics Consortium and the Department of Physiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada

Ubiquitin-specific protease 8 (USP8) hydrolyzes mono and polyubiquitylated targets such as epidermal growth factor receptors and is involved in clathrin-mediated internalization. In 1182 residues, USP8 contains multiple domains, including coiled-coil, rhodanese, and catalytic domains. We report the first high-resolution crystal structures of these domains and discuss their implications for USP8 function. The amino-terminal domain is a homodimer with a novel fold. It is composed of two five-helix bundles, where the first helices are swapped, and carboxyl-terminal helices are extended in an antiparallel fashion. The structure of the rhodanese domain, determined in complex with the E3 ligase NRDP1, reveals the canonical rhodanese fold but with a distorted primordial active site. The USP8 recognition domain of NRDP1 has a novel protein fold that interacts with a conserved peptide loop of the rhodanese domain. A consensus sequence of this loop is found in other NRDP1 targets, suggesting a common mode of interaction. The structure of the carboxyl-terminal catalytic domain of USP8 exhibits the conserved tripartite architecture but shows unique traits. Notably, the active site, including the ubiquitin binding pocket, is in a closed conformation, incompatible with substrate binding. The presence of a zinc ribbon subdomain near the ubiquitin binding site further suggests a polyubiquitin-specific binding site and a mechanism for substrate induced conformational changes.

Received for publication, July 14, 2006 , and in revised form, October 5, 2006.

The atomic coordinates and structure factors (codes 1WHB, 1WFW, 1A9U, 2GWF, 2FZP, and 2GFO) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Structural Genomics Consortium with funds from Genome Canada through the Ontario Genomics Institute, the Canadian Institutes for Health Research, the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, the Ontario Innovation Trust, the Wellcome Trust, GlaxoSmithKline, the Knut and Alice Wallenberg Foundation, and Vinnova and Swedish Foundation for Strategic Research. 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. 1S and 2S.

¹ To whom correspondence should be addressed: Structural Genomics Consortium and the Dept. of Physiology, University of Toronto, 100 College St., Toronto, ON M5G 1L5, Canada. Tel.: 416-946-3876; Fax: 416-946-0588; E-mail: sirano.dhepaganon{at}utoronto.ca.

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