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

• Published in: The Journal of biological chemistry Vol. 283; no. 39; pp. 26436 - 26443
• Main Authors: Winborn, Brett J., Travis, Sue M., Todi, Sokol V., Scaglione, K. Matthew, Xu, Ping, Williams, Aislinn J., Cohen, Robert E., Peng, Junmin, Paulson, Henry L.
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 26.09.2008
• Subjects: Protein Synthesis, Post-Translational Modification, and Degradation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M803692200

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 Lys 48 - or Lys 63 -linked chains yet preferentially cleaves Lys 63 linkages. Ataxin-3 shows even greater activity toward mixed linkage polyubiquitin, cleaving Lys 63 linkages in chains that contain both Lys 48 and Lys 63 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.