Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3.
Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3.
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DOI：
10.1371/journal.pone.0043563
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rego AC
中科院分区：
文献类型：
--
作者：
Laço MN;Cortes L;Travis SM;Paulson HL;Rego AC
泛素-蛋白酶体系统（UPS）的改变已经在以蛋白质错误折叠和聚集为特征的几种神经退行性疾病（包括聚谷氨酰胺疾病）中报道。Machado-Joseph病（MJD）或脊髓小脑共济失调3型是由ATXN 3基因中编码多聚谷氨酰胺的CAG扩增引起的，ATXN 3基因编码42 kDa的去泛素化酶（DUB），共济失调蛋白-3。我们研究了共济失调蛋白-3去泛素化活性和共济失调蛋白-3与先前描述的与共济失调蛋白-3相互作用的两种蛋白质，hHR 23 A和含valosin蛋白（VCP/p97）的相互作用的功能相关性。我们证实了共济失调蛋白-3对hHR 23 A和VCP/p97的亲和力。hHR 23 A和共济失调蛋白-3共定位于离散的核灶中，而VCP/p97主要位于细胞质中。在体外去遍在蛋白化测定中，将hHR 23 A和VCP/p97重组蛋白单独或一起添加到正常和扩增的共济失调蛋白-3中，以评估它们对共济失调蛋白-3活性的影响。VCP/p97被证明是野生型共济失调蛋白-3的特异性激活剂，对扩增的共济失调蛋白-3没有表现出影响。相反，我们观察到在单独的hHR 23 A或与VCP组合存在下，共济失调蛋白-3酶动力学或底物偏好没有显著改变。基于我们的研究结果，我们提出了一个模型，在该模型中，共济失调蛋白-3通常与其相互作用物一起发挥作用，以指定泛素化蛋白的细胞命运。
Alterations in the ubiquitin-proteasome system (UPS) have been reported in several neurodegenerative disorders characterized by protein misfolding and aggregation, including the polylgutamine diseases. Machado-Joseph disease (MJD) or Spinocerebellar Ataxia type 3 is caused by a polyglutamine-encoding CAG expansion in the ATXN3 gene, which encodes a 42 kDa deubiquitinating enzyme (DUB), ataxin-3. We investigated ataxin-3 deubiquitinating activity and the functional relevance of ataxin-3 interactions with two proteins previously described to interact with ataxin-3, hHR23A and valosin-containing protein (VCP/p97). We confirmed ataxin-3 affinity for both hHR23A and VCP/p97. hHR23A and ataxin-3 were shown to co-localize in discrete nuclear foci, while VCP/p97 was primarily cytoplasmic. hHR23A and VCP/p97 recombinant proteins were added, separately or together, to normal and expanded ataxin-3 in in vitro deubiquitination assays to evaluate their influence on ataxin-3 activity. VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3, In contrast, we observed no significant alterations in ataxin-3 enzyme kinetics or substrate preference in the presence of hHR23A alone or in combination with VCP. Based on our results we propose a model where ataxin-3 normally functions with its interactors to specify the cellular fate of ubiquitinated proteins.
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影响因子：
16
作者：
Cohn, Martin A.;Kowal, Przemyslaw;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
5.6
作者：
Kang, Yang;Chen, Xiang;Walters, Kylie J.
通讯作者：
Walters, Kylie J.
影响因子：
4.7
作者：
Diaz-Hernandez, Miguel;Valera, Adriana G.;Lucas, Jose J.
通讯作者：
Lucas, Jose J.
影响因子：
5.3
作者：
Bichelmeier, Ulrike;Schmidt, Thorsten;Riess, Olaf
通讯作者：
Riess, Olaf
影响因子：
3.5
作者：
Burnett, B;Li, FS;Pittman, RN
通讯作者：
Pittman, RN