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

Winborn, Brett J.; Travis, Sue M.; Todi, Sokol V.; Scaglione, K. Matthew; Xu, Ping; Williams, Ann E.; Cohen, Robert E.; Peng, Junmin; Paulson, Henry L.

doi:10.1074/jbc.m803692200

Cited by 236 publications

(332 citation statements)

References 55 publications

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“…Although the tandem UIMs in Ataxin-3, a DUB of the Ataxin-3/Josephin family, bind equally to Lys 48 -and Lys 63 -linked ubiquitin chains, this DUB selectively cleaves Lys 63 -linked chains (24). When the UIMs are mutated, Ataxin-3 loses substrate specificity and cleaves Lys 48 and Lys 63 ubiquitin chains with similar efficiency, suggesting that in Ataxin-3, the UIMs play a role in rendering the ubiquitin chain substrate specificity, rather than increasing the catalytic activity, toward Lys 63 -linked ubiquitin chains (24).…”

Section: ⌬Uim3mentioning

confidence: 99%

Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Tanno

Shigematsu

Nishikawa

et al. 2014

Journal of Biological Chemistry

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Background:The role of ubiquitin-interacting motifs (UIMs) in the deubiquitinating enzyme USP37 is unknown. Results: Inactivation of the UIMs in USP37 resulted in lower isopeptidase activity toward ubiquitin chains. Conclusion: The UIMs in USP37 are required for the full catalytic activity of the enzyme. Significance: This study reveals a novel mechanism to increase the catalytic activity of deubiquitinating enzymes.

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Section: ⌬Uim3mentioning

confidence: 99%

Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Tanno

Shigematsu

Nishikawa

et al. 2014

Journal of Biological Chemistry

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“…It was demonstrated to hydrolyze both free Ub chains and Ub conjugates from the U-box E3 CHIP, another recently identified substrate for ataxin-3 (31,32). Indeed, by deubiquitinating CHIP, ataxin-3 regulates the ligase activity of CHIP, whereas at the same time trimming newly forming Ub chains on CHIP substrates.…”

Section: Ataxin-3 Deubiquitinates Parkin In An Unconventionalmentioning

confidence: 99%

Ataxin-3 Deubiquitination Is Coupled to Parkin Ubiquitination via E2 Ubiquitin-conjugating Enzyme

Durcan

Kontogiannea

Bédard

et al. 2012

Journal of Biological Chemistry

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Background:The deubiquitinating enzyme (DUB) ataxin-3 opposes the E3 ubiquitin-ligase activity of parkin, however, the mechanism involved is unclear. Results: Ataxin-3 opposes parkin ubiquitination by regulating the E2 ubiquitin-conjugating enzyme. Conclusion: The components within a E2⅐E3⅐DUB complex are functionally coupled to fine-tune the overall extent of ubiquitination. Significance: The work broadens our understanding of the intricate interplay between E3s, DUBs, and the ubiquitination machinery.

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“…Furthermore, Cezanne preferentially cleaves Lys11 over Lys48 and Lys63 linkages (Bremm et al, 2010), whereas JAMMs share the specificity for Lys63-linked polyubiquitin (McCullough et al, 2004;Sato et al, 2008;Cooper et al, 2009). Finally, the Josephin ATXN3-editing activity shows a restricted specificity for K63-linked chains (Winborn et al, 2008).…”

Section: Enzymatic Roles and Regulation 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 Deubiquitinating Enzyme Ataxin-3, a Polyglutamine Disease Protein, Edits Lys63 Linkages in Mixed Linkage Ubiquitin Chains

Cited by 236 publications

References 55 publications

Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Ubiquitin-interacting Motifs Confer Full Catalytic Activity, but Not Ubiquitin Chain Substrate Specificity, to Deubiquitinating Enzyme USP37

Ataxin-3 Deubiquitination Is Coupled to Parkin Ubiquitination via E2 Ubiquitin-conjugating Enzyme

Deubiquitinases in cancer: new functions and therapeutic options

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