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
TLDR
It is reported 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.Abstract:
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 proteolytic 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.read more
Citations
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The Ubiquitin Code
David Komander,Michael Rape +1 more
TL;DR: The structure, assembly, and function of the posttranslational modification with ubiquitin, a process referred to as ubiquitylation, controls almost every process in cells.
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The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg.
Aaron Ciechanover,Patrik Brundin +1 more
TL;DR: Recent findings indicate that the ubiquitin-proteasome system is involved in the pathogenesis of Parkinson's, Alzheimer's, Huntington's, and Prion diseases as well as amyotrophic lateral sclerosis, which raises hopes for a better understanding of the pathogenetic mechanisms involved in these diseases and for the development of novel, mechanism-based therapeutic modalities.
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Sequestosome 1/p62 Is a Polyubiquitin Chain Binding Protein Involved in Ubiquitin Proteasome Degradation
M. Lamar Seibenhener,Jeganathan Ramesh Babu,Thangiah Geetha,Hing C. Wong,N. Rama Krishna,Marie W. Wooten +5 more
TL;DR: The results support the hypothesis that p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation.
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Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions.
TL;DR: The reported biological functions of VCP are summarized and the molecular mechanisms underlying the diverse cellular functions are explored, and how this sophisticated enzymatic machine converts chemical energy into the mechanical forces required for the chaperone activity is elucidated.
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ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology
Yung C. Lam,Aaron B. Bowman,Paymaan Jafar-Nejad,Janghoo Lim,Ronald Richman,John D. Fryer,Eric D. Hyun,Lisa A. Duvick,Harry T. Orr,Juan Botas,Huda Y. Zoghbi +10 more
TL;DR: In this paper, the authors examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua.
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