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A key lysine residue in the AXH domain of ataxin-1 is essential for its ubiquitylation
- Source :
- Biochimica et biophysica acta. 1854(5)
- Publication Year :
- 2014
-
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.
- Subjects :
- Models, Molecular
Lysine
Mutant
Biophysics
Ataxin 1
Nerve Tissue Proteins
Protein degradation
Biology
Protein aggregation
Biochemistry
Analytical Chemistry
Protein Aggregates
Ubiquitin
medicine
Humans
Amino Acid Sequence
Molecular Biology
Ataxin-1
Binding Sites
Neurodegeneration
Ubiquitination
Nuclear Proteins
Polyglutamine tract
medicine.disease
Protein Structure, Tertiary
HEK293 Cells
Ataxins
Ubiquitin-Conjugating Enzymes
biology.protein
Mutagenesis, Site-Directed
Mutant Proteins
Protein Binding
Subjects
Details
- ISSN :
- 00063002
- Volume :
- 1854
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Biochimica et biophysica acta
- Accession number :
- edsair.doi.dedup.....69b7e9a7933c53220ed919ce105e0329