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.
authors: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors: A-ram
authors: AR
authors: Kang
authors: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors: Si Hoon
authors: SH
authors: Park
authors: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors: Soyeon
authors: S
authors: Lee
authors: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors: Do-Young
authors: DY
authors: Choi
authors: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors: Kwang Pyo
authors: KP
authors: Kim
authors: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors: Hyun Kyu
authors: HK
authors: Song
authors: Clinical Laboratory Science, College of Health Sciences, Korea University, Seoul 136-703, Republic of Korea.
authors: Sunghoi
authors: S
authors: Hong
authors: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea. Electronic address: skang@korea.ac.kr.
authors: Seongman
authors: S
authors: Kang
mesh_terms: D000595:Amino Acid Sequence; D000067696:Ataxin-1; D000067528:Ataxins; D001665:Binding Sites / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D066329:Protein Aggregates; C489963:UBE2E1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D008239:Lysine
keywords: Ataxin-1; Protein aggregation; Protein degradation; Spinocerebellar ataxia type 1 (SCA1); UbcH6; Ubiquitylation