The mechanism of poly-NEDD8 chain formation in vitro

Ohki, Yu; Funatsu, Norikazu; Konishi, Natsumi; Chiba, Tomoki

doi:10.1016/j.bbrc.2009.02.090

Cited by 36 publications

(31 citation statements)

References 17 publications

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“…Moreover, it was found that NEDD8 can form chains through Lys11, Lys22, Lys27, Lys48, Lys54 and Lys60 59–62 . NEDD8 chains could pre-form on the active site of UBC12 57 .…”

Section: Mechanism Of Neddylation and Deneddylationmentioning

confidence: 99%

Protein neddylation: beyond cullin–RING ligases

Enchev

Schulman

Peter

2014

Nat Rev Mol Cell Biol

457

513

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NEDD8 is a ubiquitin-like protein that activates the largest ubiquitin E3 ligase family, the cullin RING ligases. Many non-cullin neddylation targets have been proposed in recent years. However, overexpression of exogenous NEDD8 can trigger NEDD8 conjugation through the ubiquitylation machinery, which makes validating potential NEDD8 targets challenging. Here we re-evaluate these studies in light of the current understanding of the neddylation pathway, and suggest criteria for the identification of genuine neddylation substrates under homeostatic conditions. We describe the biological processes that might be regulated by non-cullin neddylation, and the utility of neddylation inhibitors for research and as potential therapies. Understanding the biological significance of non-cullin neddylation is an exciting research prospect primed to reveal fundamental insights.

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“…Moreover, it was found that NEDD8 can form chains through Lys11, Lys22, Lys27, Lys48, Lys54 and Lys60 59–62 . NEDD8 chains could pre-form on the active site of UBC12 57 .…”

Section: Mechanism Of Neddylation and Deneddylationmentioning

confidence: 99%

Protein neddylation: beyond cullin–RING ligases

Enchev

Schulman

Peter

2014

Nat Rev Mol Cell Biol

457

513

View full text Add to dashboard Cite

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“…Examples of both contradictory and concordant evidence lead to debate about the chain-forming ability of Rub1 (75)(76)(77)(78). Ub has seven lysine residues (K6, K11, K27, K29, K33, K48, and K63), and all of them have been shown to be involved in chain formation in vivo (79 -81).…”

Section: Recognition and Cleavage Of Rub1-ubiquitin Chainsmentioning

confidence: 99%

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

Singh

Zerath

Kleifeld

et al. 2012

Molecular & Cellular Proteomics

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Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show via NMR that structurally, Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 and of ubiquitin as modifiers of the proteome is starkly different, and their attachments to specific substrates perform different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/ Nedd8 and ubiquitin within cells. To understand whether and how it might be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined whether ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin but binds more weakly to a proteasomal ubiquitin receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin shuttles and receptors comparably to K48-linked ubiquitin homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to the actions of other canonical deubiquitinating enzymes. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin pathways, it is recognized essentially like The selective degradation of many proteins in eukaryotic cells is a highly specific and irreversible process required to perform vital cellular functions such as cell cycle progression (1, 2), differentiation and development (3, 4), and transcriptional control (5). One of the major pathways involved in this selective degradation is the ubiquitin-proteasome pathway. In this pathway, ubiquitin (Ub), a 76-amino-acid protein, is attached to the substrate, and this is followed by the recognition and degradation of the substrate by a protein complex collectively known as proteasome (6 -8).The attachment of Ub (ubiquitination) to a substrate protein is achieved via a cascade of enzymatic reactions (involving E1, E2, and E3 enzymes) that results in the formation of an isopeptide bond between the C-terminal glycine of Ub and a lysine residue of the substrate (9 -11). Sequential repetition of this cascade can result in the attachment of a chain of Ub molecules (polyubiquitin) to the substrate protein. The length and topology of the polyubiquitin (polyUb) tag decide the fate of the substrate protein. For example, we and others have shown that a K48-linked tetraubiquitin (tetraUb) chain that acts as a proteasomal degradation signal forms a "closed" structure (12, 13), whereas a K63-linked Ub...

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“…NEDD 8 has a highest homology to ubiquitin and is conserved among a wide range of organisms such as yeast, plants, and mammals [10][11][12][13]. The process of neddylation is involved in various cellular functions including cell cycle progression [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

Yang

Joo

Hong

et al. 2010

Korean J Physiol Pharmacol

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Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease.

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The mechanism of poly-NEDD8 chain formation in vitro

Cited by 36 publications

References 17 publications

Protein neddylation: beyond cullin–RING ligases

Protein neddylation: beyond cullin–RING ligases

Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System

Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice

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