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 language | English |
|---|---|
| Pages (from-to) | 356-364 |
| Number of pages | 9 |
| Journal | Biochimica et Biophysica Acta - Proteins and Proteomics |
| Volume | 1854 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2015 |
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Keywords
- Ataxin-1
- Protein aggregation
- Protein degradation
- Spinocerebellar ataxia type 1 (SCA1)
- UbcH6
- Ubiquitylation
ASJC Scopus subject areas
- Biochemistry
- Biophysics
- Analytical Chemistry
- Molecular Biology
Cite this
A key lysine residue in the AXH domain of ataxin-1 is essential for its ubiquitylation. / Kang, A. Ram; Park, Si Hoon; Lee, Soyeon; Choi, Do Young; Kim, Kwang Pyo; Song, Hyun Kyu; Hong, Sunghoi; Kang, Seong Man.
In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1854, No. 5, 2015, p. 356-364.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A key lysine residue in the AXH domain of ataxin-1 is essential for its ubiquitylation
AU - Kang, A. Ram
AU - Park, Si Hoon
AU - Lee, Soyeon
AU - Choi, Do Young
AU - Kim, Kwang Pyo
AU - Song, Hyun Kyu
AU - Hong, Sunghoi
AU - Kang, Seong Man
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Ataxin-1
KW - Protein aggregation
KW - Protein degradation
KW - Spinocerebellar ataxia type 1 (SCA1)
KW - UbcH6
KW - Ubiquitylation
UR - http://www.scopus.com/inward/record.url?scp=84922569246&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922569246&partnerID=8YFLogxK
U2 - 10.1016/j.bbapap.2015.01.012
DO - 10.1016/j.bbapap.2015.01.012
M3 - Article
C2 - 25641559
AN - SCOPUS:84922569246
VL - 1854
SP - 356
EP - 364
JO - Biochimica et Biophysica Acta - Proteins and Proteomics
JF - Biochimica et Biophysica Acta - Proteins and Proteomics
SN - 1570-9639
IS - 5
ER -