Deubiquitinating function of ataxin-3: Insights from the solution structure of the Josephin domain

Mao, Yuxin; Senic-Matuglia, Francesca; Fiore, Pier Paolo Di; Polo, Simona; Hodsdon, Michael E.; Camilli, Pietro De

doi:10.1073/pnas.0506344102

Cited by 147 publications

(139 citation statements)

References 41 publications

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“…Although the solution structure of the Josephin domain has been solved (24,52,53), the structures of the carboxyl-terminal ubiquitin-binding region and the full protein have not.…”

Section: Discussionmentioning

confidence: 99%

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The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

Winborn

Travis

Todi

et al. 2008

Journal of Biological Chemistry

238

320

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Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin chain preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a manner suggesting that it functions as a mixed linkage, chain-editing enzyme. Ataxin-3 cleaves ubiquitin chains through its amino-terminal Josephin domain and binds ubiquitin chains through a carboxyl-terminal cluster of ubiquitin interaction motifs neighboring the pathogenic polyglutamine tract.

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“…Although the solution structure of the Josephin domain has been solved (24,52,53), the structures of the carboxyl-terminal ubiquitin-binding region and the full protein have not.…”

Section: Discussionmentioning

confidence: 99%

“…1A) (19,20). Mutating the catalytic cysteine residue (Cys 14 ) in ataxin-3 abolishes protease activity, whereas mutating conserved residues in the UIMs diminishes ubiquitin chain binding (21)(22)(23)(24). The polyQ tract, which is expanded in persons afflicted with spinocerebellar ataxia type 3, resides between the second and third UIMs.…”

mentioning

confidence: 99%

The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

Winborn

Travis

Todi

et al. 2008

Journal of Biological Chemistry

238

320

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show abstract

“…This protein acts as a polyubiquitin chain-editing enzyme controlling protein folding and stability (Mao et al, 2005). Furthermore, its ubiquitin hydrolase activity is essential for a normal lifespan, thereby demonstrating that ubiquitin chain editing contributes to longevity regulation (Kuhlbrodt et al, 2011).…”

Section: The Large and Complex Group Of Dubsmentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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“…The crystal structure of the ataxin-3 JD provided insight into the potential function of ataxin-3 as a polyubiquitin chain editing protein by demonstrating a tight connection between polyubiquitin binding and the deubiquitylating activity of ataxin-3 (Mao et al 2005;Nicastro et al 2005). Thus, there are considerable structural data indicating that ataxin-3 has a role in the ubiquitin and/or the ubiquitin-proteasome system.…”

Section: Sca3: a Link To Ubiquitin-proteasome Regulation Of Transcripmentioning

confidence: 99%

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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Deubiquitinating function of ataxin-3: Insights from the solution structure of the Josephin domain

Cited by 147 publications

References 41 publications

The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

The Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

Deubiquitinases in cancer: new functions and therapeutic options

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

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