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The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.

Publication ,  Journal Article
Winborn, BJ; Travis, SM; Todi, SV; Scaglione, KM; Xu, P; Williams, AJ; Cohen, RE; Peng, J; Paulson, HL
Published in: J Biol Chem
September 26, 2008

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.

Duke Scholars

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 26, 2008

Volume

283

Issue

39

Start / End Page

26436 / 26443

Location

United States

Related Subject Headings

  • Ubiquitin Thiolesterase
  • Ubiquitin
  • Repressor Proteins
  • Protein Structure, Tertiary
  • Peptides
  • Nuclear Proteins
  • Nerve Tissue Proteins
  • Humans
  • Heredodegenerative Disorders, Nervous System
  • Cell Line
 

Citation

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Winborn, B. J., Travis, S. M., Todi, S. V., Scaglione, K. M., Xu, P., Williams, A. J., … Paulson, H. L. (2008). The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem, 283(39), 26436–26443. https://doi.org/10.1074/jbc.M803692200
Winborn, Brett J., Sue M. Travis, Sokol V. Todi, K Matthew Scaglione, Ping Xu, Aislinn J. Williams, Robert E. Cohen, Junmin Peng, and Henry L. Paulson. “The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.J Biol Chem 283, no. 39 (September 26, 2008): 26436–43. https://doi.org/10.1074/jbc.M803692200.
Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, et al. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem. 2008 Sep 26;283(39):26436–43.
Winborn, Brett J., et al. “The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.J Biol Chem, vol. 283, no. 39, Sept. 2008, pp. 26436–43. Pubmed, doi:10.1074/jbc.M803692200.
Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem. 2008 Sep 26;283(39):26436–26443.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

September 26, 2008

Volume

283

Issue

39

Start / End Page

26436 / 26443

Location

United States

Related Subject Headings

  • Ubiquitin Thiolesterase
  • Ubiquitin
  • Repressor Proteins
  • Protein Structure, Tertiary
  • Peptides
  • Nuclear Proteins
  • Nerve Tissue Proteins
  • Humans
  • Heredodegenerative Disorders, Nervous System
  • Cell Line