Dcn1 Functions as a Scaffold-Type E3 Ligase for Cullin Neddylation

Kurz, Thimo; Chou, Yang-Chieh; Willems, Andrew; Meyer-Schaller, Nathalie; Hecht, Marie-Lyn; Tyers, Mike; Peter, Matthias; Sicheri, Frank

doi:10.1016/j.molcel.2007.12.012

Cited by 167 publications

(202 citation statements)

References 51 publications

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“…Thus, the Ubc12 sites for binding to Smurf1 appear to largely overlap with that for the E1. The previously identified Nedd8 ligation-promoting factor Dcn1 binds Ubc12 in the same pattern 23 . In addition, deletion analysis indicated that the Smurf1 HECT N-lobe small subdomain mediated the interaction with Ubc12 (Fig.…”

Section: Smurf1 Interacts Withmentioning

confidence: 66%

“…Smurf1 can be neddylated by itself or by other Nedd8 ligase(s). Among the currently known Nedd8 ligases (that is, Dcn1, Roc1/ Rbx1, MDM2, IAPs and c-Cbl) 6,13,23,25,[39][40][41][42] , only MDM2 was demonstrated to interact with Smurf1 (ref. 43).…”

Section: Smurf1 Interacts Withmentioning

confidence: 99%

“…For example, Roc1/ Rbx1 and Dcn1 function synergistically to promote Nedd8 transfer from Ubc12 to Cullins 23,24 . MDM2, c-Cbl and IAPs have also been demonstrated to function as Nedd8 ligases to promote ligation to non-Cullin proteins 6,7,13,25 .…”

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confidence: 99%

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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

et al. 2014

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Neddylation, the covalent attachment of ubiquitin-like protein Nedd8, of the Cullin-RING E3 ligase family regulates their ubiquitylation activity. However, regulation of HECT ligases by neddylation has not been reported to date. Here we show that the C2-WW-HECT ligase Smurf1 is activated by neddylation. Smurf1 physically interacts with Nedd8 and Ubc12, forms a Nedd8-thioester intermediate, and then catalyses its own neddylation on multiple lysine residues. Intriguingly, this autoneddylation needs an active site at C426 in the HECT N-lobe. Neddylation of Smurf1 potently enhances ubiquitin E2 recruitment and augments the ubiquitin ligase activity of Smurf1. The regulatory role of neddylation is conserved in human Smurf1 and yeast Rsp5. Furthermore, in human colorectal cancers, the elevated expression of Smurf1, Nedd8, NAE1 and Ubc12 correlates with cancer progression and poor prognosis. These findings provide evidence that neddylation is important in HECT ubiquitin ligase activation and shed new light on the tumour-promoting role of Smurf1.

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Section: Smurf1 Interacts Withmentioning

confidence: 66%

Section: Smurf1 Interacts Withmentioning

confidence: 99%

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The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

et al. 2014

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“…Additionally, there was a putative Rad53 binding site. Recently, researchers uncovered a novel MEC1-RAD53-DCN1-dependent signaling pathway that prevented deleterious DSB-specific telomerase additions at DNA breaks, thus preserving genomic integrity (Makovets et al, 2009;Kurz et al, 2008). Taken together, these findings suggested that the DCUN1D5 might play a role in DNA damage response to genotoxic stress and probably subsequent DNA repair.…”

Section: Discussionmentioning

confidence: 97%

In Vitro Biological Characterization of DCUN1D5 in DNA Damage Response

Wei

Li²,

Xu³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: Novel prognostic biomarkers or therapeutic molecular targets for laryngeal squamous cell carcinoma (LSCC) are an urgent priority. We here sought to identify multiple novel LSCC-associated genes. Methods: Using high-density microarray expression profiling, we identified multiple genes that were significantly altered between human LSCCs and paired normal tissues. Potential oncogenic functions of one such gene, DCUN1D5, were further characterized in vitro. Results: Our results demonstrated that DCUN1D5 was highly expressed in LSCCs. Overexpression of DCUN1D5 in vitro resulted in 2.7-fold increased cellular migration, 67.5% increased invasive capacity, and 2.6-fold increased proliferation. Endogenous DCUN1D5 expression was decreased in a time-dependent manner after genotoxic stress, and silencing of DCUN1D5 by siRNA decreased the number of cells in the S phase by 10.2% and increased apoptosis by 11.7%. Conclusion: Our data suggest that DCUN1D5 in vitro might have vital roles in DNA damage response, but further studies are warranted to assess its significance in vivo.

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“…Early studies demonstrated that cullin neddylation is required for efficient ubiquitylation and/or turnover of CRL substrates in vivo, which has been borne out through the development of MLN4924, a small-molecule inhibitor of NAE [14,[48][49][50]. Inhibition of CRL activity by MLN4924 results in accumulation of a host of CRL targets [14,43,51,52].Structural and biochemical studies revealed a complex mechanism underlying cullin neddylation that involves dual E3 activity and co-translational modification of neddylation E2s to strongly activate the transfer of NEDD8 to the cullin [39,44,53,54]. Early studies indicated that UBC12 can neddylate CUL1 in vitro in a manner that requires RBX1 [55][56][57] For simplicity, therefore, we refer to Cdc53 as yeast CUL1 throughout.…”

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confidence: 99%

Building and remodelling Cullin–RING E3 ubiquitin ligases

2013

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Cullin-RING E3 ubiquitin ligases (CRLs) control a plethora of biological pathways through targeted ubiquitylation of signalling proteins. These modular assemblies use substrate receptor modules to recruit specific targets. Recent efforts have focused on understanding the mechanisms that control the activity state of CRLs through dynamic alterations in CRL architecture. Central to these processes are cycles of cullin neddylation and deneddylation, as well as exchange of substrate receptor modules to re-sculpt the CRL landscape, thereby responding to the cellular requirements to turn over distinct proteins in different contexts. This review is focused on how CRLs are dynamically controlled with an emphasis on how c ullin neddylation cycles are integrated with receptor exchange. Keywords: cullin; ubiquitin; Nedd8; COP9 signalosome; E3 ligase; CAND1 EMBO reports (2013) 14, 1050-1061 published online 15 November 2013; doi:10.1038/embor.2013 See the Glossary for abbreviations used in this article. IntroductionThe proteome is constantly remodelled to suit the needs of the cell, through both synthesis and turnover. Protein turnover is controlled through two main systems: the ubiquitin-proteasome system (UPS) and lysosomal degradation system, including autophagy. Although selective autophagy can provide a means by which to control the abundance of particular organelles and even single proteins, it is best understood as a means to control bulk turnover of cellular components [1]. Conversely, the UPS is a particularly versatile and highly regulated system [2] that allows selective turnover of individual regulatory proteins, even when they are incorporated into higher-order multiprotein assemblies. On the one hand, the entire population of a given protein targeted by the UPS might be subject to rapid tagging with ubiquitin and degradation by the proteasome. On the other hand, the UPS might control the degradation of only a small pool of a particular target protein, for example the population of a protein that has been phosphorylated by an upstream pathway. Thus, the UPS functions in space and time to sculpt the proteome and to control the abundance of active or inactive forms of signalling complexes and cellular machines. As illustrated in this Review, the UPS machinery that controls turnover of a wide swathe of the p roteome is itself dynamically regulated through many mechanisms.The tagging of proteins with particular types of ubiquitin chains serves to mark them for proteasomal degradation. This process occurs through an E1 (ubiquitin-activating enzyme)-E2 (ubiquitinconjugating enzyme)-E3 (ubiquitin ligase) cascade [3][4][5][6][7]. E3 plays a central role in substrate targeting by binding directly to the substrate and presenting target lysine residues to receive ubiquitin from the E2, in the case of RING E3s, or from a ubiquitin-charged cysteine residue in HECT and RBR E3s [6,[8][9][10]. Cullin-RING E3 ubiquitin ligases (CRLs), which were first discovered almost two decades ago [11][12][13], are a superfamily of RING E3...

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Dcn1 Functions as a Scaffold-Type E3 Ligase for Cullin Neddylation

Cited by 167 publications

References 51 publications

The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

The covalent modifier Nedd8 is critical for the activation of Smurf1 ubiquitin ligase in tumorigenesis

In Vitro Biological Characterization of DCUN1D5 in DNA Damage Response

Building and remodelling Cullin–RING E3 ubiquitin ligases

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