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

doi:10.1016/j.bbapap.2015.01.012

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 journal › Article › peer-review

10 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 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	https://doi.org/10.1016/j.bbapap.2015.01.012
Publication status	Published - 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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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, Seongman.

In: Biochimica et Biophysica Acta - Proteins and Proteomics, Vol. 1854, No. 5, 05.2015, p. 356-364.

Research output: Contribution to journal › Article › peer-review

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

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.",

keywords = "Ataxin-1, Protein aggregation, Protein degradation, Spinocerebellar ataxia type 1 (SCA1), UbcH6, Ubiquitylation",

author = "Kang, {A. Ram} and Park, {Si Hoon} and Soyeon Lee and Choi, {Do Young} and Kim, {Kwang Pyo} and Song, {Hyun Kyu} and Sunghoi Hong and Seongman Kang",

note = "Funding Information: We are grateful to Dr. H. T. Orr (Institute of Human Genetics, University of Minnesota) for providing the plasmids containing ATXN1(30Q) or (82Q). This work was supported by the National Research Foundation of Korea (NRF) grant (MEST) ( 2012R1A2A2A01002919 ) and by a grant from the National R&D Program for Cancer Control, the Ministry of Health & Welfare ( 1320010 ), Republic of Korea. Publisher Copyright: {\textcopyright} 2015 Elsevier B.V. All rights reserved.",

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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, Seongman

N1 - Funding Information: We are grateful to Dr. H. T. Orr (Institute of Human Genetics, University of Minnesota) for providing the plasmids containing ATXN1(30Q) or (82Q). This work was supported by the National Research Foundation of Korea (NRF) grant (MEST) ( 2012R1A2A2A01002919 ) and by a grant from the National R&D Program for Cancer Control, the Ministry of Health & Welfare ( 1320010 ), Republic of Korea. Publisher Copyright: © 2015 Elsevier B.V. All rights reserved.

PY - 2015/5

Y1 - 2015/5

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.

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KW - Protein aggregation

KW - Protein degradation

KW - Spinocerebellar ataxia type 1 (SCA1)

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JO - Biochimica et Biophysica Acta - Proteins and Proteomics

JF - Biochimica et Biophysica Acta - Proteins and Proteomics

SN - 1570-9639

IS - 5

ER -

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

Abstract

Keywords

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