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; Henry L Paulson

doi:10.1074/jbc.M803692200

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

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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 Paulson

The Journal of biological chemistry, Vol.283(39), pp.26436-26443

09/26/2008

DOI: 10.1074/jbc.M803692200

PMCID: PMC2546540

PMID: 18599482

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Abstract

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.

Details

Title: Subtitle: The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys⁶³ Linkages in Mixed Linkage Ubiquitin Chains
Creators: Brett J Winborn - Department of Neurology, University of Michigan, Ann Arbor, Michigan 48108
Sue M Travis - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Sokol V Todi - Department of Neurology, University of Michigan, Ann Arbor, Michigan 48108
K. Matthew Scaglione - Department of Neurology, University of Michigan, Ann Arbor, Michigan 48108
Ping Xu - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
Aislinn J Williams - Program in Neuroscience and Medical Scientist Training Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Robert E Cohen - Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205
Junmin Peng - Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322
Henry L Paulson - Program in Molecular and Cellular Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.283(39), pp.26436-26443
DOI: 10.1074/jbc.M803692200
PMID: 18599482
PMCID: PMC2546540
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Grant note: NS038712; AG025688 / National Institutes of Health National Ataxia Foundation
Language: English
Date published: 09/26/2008
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984066393802771

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