Journal of Biological Chemistry
Volume 283, Issue 39, 26 September 2008, Pages 26436-26443
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Protein Synthesis, Post-Translational Modification, and Degradation
The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains*

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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.

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*

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.