Ataxin-3 interactions with Rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis

被引:179
作者
Doss-Pepe, EW
Stenroos, ES
Johnson, WG
Madura, K [1 ]
机构
[1] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem, Piscataway, NJ 08854 USA
[2] Univ Med & Dent New Jersey, Dept Neurol, Piscataway, NJ 08854 USA
关键词
D O I
10.1128/MCB.23.18.6469-6483.2003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Machado-Joseph disease is caused by an expansion of a trinucleotide CAG repeat in the gene encoding the protein ataxin-3. We investigated if ataxin-3 was a proteasome-associated factor that recognized ubiquitinated substrates based on the rationale that (i) it is present with proteasome subunits and ubiquitin in cellular inclusions, (ii) it interacts with human Rad23, a protein that may translocate proteollytic substrates to the proteasome, and (iii) it shares regions of sequence similarity with the proteasome subunit S5a, which can recognize multiubiquitinated proteins. We report that ataxin-3 interacts with ubiquitinated proteins, can bind the proteasome, and, when the gene harbors an expanded repeat length, can interfere with the degradation of a well-characterized test substrate. Additionally, ataxin-3 associates with the ubiquitin- and proteasome-binding factors Rad23 and valosin-containing protein (VCP/p97), findings that support the hypothesis that ataxin-3 is a proteasome-associated factor that mediates the degradation of ubiquitinated proteins.
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页码:6469 / 6483
页数:15
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