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J. Biol. Chem., Vol. 283, Issue 39, 26436-26443, September 26, 2008

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The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys⁶³ Linkages in Mixed Linkage Ubiquitin Chains^*

Brett J. Winborn^¶, Sue M. Travis, Sokol V. Todi^¶, K. Matthew Scaglione^¶, Ping Xu^||, Aislinn J. Williams^**, Robert E. Cohen, Junmin Peng^||, and Henry L. Paulson¹

From the Program in Molecular and Cellular Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, the Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, the ^¶Department of Neurology, University of Michigan, Ann Arbor, Michigan 48108, the ^||Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, the ^**Program in Neuroscience and Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, and the Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin chain preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a manner suggesting that it functions as a mixed linkage, chain-editing enzyme. Ataxin-3 cleaves ubiquitin chains through its amino-terminal Josephin domain and binds ubiquitin chains through a carboxyl-terminal cluster of ubiquitin interaction motifs neighboring the pathogenic polyglutamine tract. Ataxin-3 binds both Lys⁴⁸- or Lys⁶³-linked chains yet preferentially cleaves Lys⁶³ linkages. Ataxin-3 shows even greater activity toward mixed linkage polyubiquitin, cleaving Lys⁶³ linkages in chains that contain both Lys⁴⁸ and Lys⁶³ linkages. The ubiquitin interaction motifs regulate the specificity of this activity by restricting what can be cleaved by the protease domain, demonstrating that linkage specificity can be determined by elements outside the catalytic domain of a DUB. These findings establish ataxin-3 as a novel DUB that edits topologically complex chains.

Received for publication, May 14, 2008 , and in revised form, July 2, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS038712 (to H. L. P.) and AG025688 (to J. P.). This work was also supported by a National Ataxia Foundation grant (to S. M. T.). 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. S1–S3 and Table S1.

¹ To whom correspondence should be addressed: Dept. of Neurology, University of Michigan, 4001 BSRB, 109 Zina Pitcher Pl., Ann Arbor, MI 48109. Fax: 734-763-7686; E-mail: henryp{at}umich.edu.

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