A key lysine residue in the AXH domain of ataxin-1 is essential for its ubiquitylation

A. Ram Kang, Si Hoon Park, Soyeon Lee, Do Young Choi, Kwang Pyo Kim, Hyun Kyu Song, Sunghoi Hong, Seongman Kang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 1 (SCA1), an autosomal-dominant neurodegenerative disorder, is caused by expansion of the polyglutamine tract within ataxin-1 (ATXN1). The AXH domain of ATXN1 can mediate neurodegeneration through its interaction with other proteins. We have previously showed that the ubiquitin-conjugating enzyme UbcH6 modulates the transcriptional repression activity of ATXN1 through ubiquitylation. In the present study, we sought to identify sites in the AXH domain that are ubiquitylated by UbcH6. Systematic replacement of each lysine residue in the AXH domain revealed that the lysine at 589 (K589) of ATXN1 is essential for its ubiquitylation by UbcH6. Mass spectrometry studies further confirmed the ubiquitylation site. Interestingly, protein aggregation was significantly enhanced in mutant AXH K589R, implying that the aggregation is strongly associated with the level of ATXN1 expression. Our study may suggest a therapeutic potential of UbcH6 in the treatment of SCA1.

Original languageEnglish
Pages (from-to)356-364
Number of pages9
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1854
Issue number5
DOIs
Publication statusPublished - 2015 May

Keywords

  • Ataxin-1
  • Protein aggregation
  • Protein degradation
  • Spinocerebellar ataxia type 1 (SCA1)
  • UbcH6
  • Ubiquitylation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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