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https://hdl.handle.net/10316/109930
Title: | Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3 | Authors: | Laço, Mário N. Cortes, Luísa Travis, Sue M. Paulson, Henry L. Rego, A. Cristina |
Issue Date: | 2012 | Publisher: | Public Library of Science | Serial title, monograph or event: | PLoS ONE | Volume: | 7 | Issue: | 9 | Abstract: | 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. | URI: | http://hdl.handle.net/10316/109930 | ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0043563 | Rights: | openAccess |
Appears in Collections: | FMUC Medicina - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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ValosinContaining-Protein-VCPp97-Is-an-Activator-of-WildType-Ataxin3PLoS-ONE.pdf | 1.97 MB | Adobe PDF | View/Open |
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