原创力文档valosin-containing protein (vcpp97) is an activator of wild-type ataxin-3valosin-containing蛋白质(vcpp97)是一种野生型ataxin-3活化剂.pdfVIP
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valosin-containing protein (vcpp97) is an activator of wild-type ataxin-3valosin-containing蛋白质(vcpp97)是一种野生型ataxin-3活化剂
Valosin-Containing Protein (VCP/p97) Is an Activator of
Wild-Type Ataxin-3
´ 1,2 1 3 4 1,2
Mario N. Lac¸o , Luisa Cortes , Sue M. Travis , Henry L. Paulson *, A. Cristina Rego *
1 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal, 2 Faculty of Medicine, University of Coimbra, Coimbra, Portugal, 3 Department of
Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America, 4 Department of Neurology, University of Michigan Medical School,
Ann Arbor, Michigan, United States of America
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 ata
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