Crystal structure of the NEMO ubiquitin‐binding domain in complex with Lys 63‐linked di‐ubiquitin

Yoshikawa, Azusa; Sato, Yusuke; Yamashita, Masami; Mimura, Hisatoshi; Yamagata, Atsushi; Fukai, Shuya

doi:10.1016/j.febslet.2009.09.028

Cited by 72 publications

(74 citation statements)

References 26 publications

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“…The side chain of one of the SUMOylation sites, K277 present in the CC2 (coil-coil 2) region of NEMO, is pointing interior toward the center of the coil-coil and appears to be inaccessible to the solvent surface [85,86,89]. This suggests that a regulatory step might be required to induce a conformational change in this CC2 region to increase its accessibility to the SUMOylation machinery (particularly the Ubc9 SUMO conjugating enzyme).…”

Section: Nemo Structural Conundrummentioning

confidence: 99%

“…Recent structural analyses of NEMO subdomains with or without different binding partners [85][86][87][88][89][90] suggest that recombinant NEMO forms an elongated parallel coiled-coil dimer that is predicted to elute in gel filtration with an apparent value of about 270 kDa [90]. Experimental evidence provided by Agou et al [91] showed that the elution profile of recombinant NEMO protein in gel filtration chromatography corresponds to a 500-kDa globular protein with a 73 Å Stokes radius.…”

Section: Nemo Structural Conundrummentioning

confidence: 99%

“…Moreover, the covalent attachment of a ~20 kDa globular SUMO1 molecule to the SUMOylation sites, particularly K277, is expected to significantly distort the coil-coil dimeric structure of NEMO, since it would sterically prevent the movement of the K277 side chain toward the interior of the coil-coil. Addition of a SUMO1 moiety to the side chain of the other SUMOylation site, K309, would also significantly affect the polyubiquitinbinding activity of the NEMO NOA/NUB/UBAN domain, since this residue is located in the middle of the ubiquitin binding patch, IYKADF [85,86,89]. Thus, SUMOylation of K277 and K309 is likely associated with significant perturbations in the NEMO structure both during and subsequent to the SUMOylation reaction.…”

Section: Nemo Structural Conundrummentioning

confidence: 99%

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Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

2010

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A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxinexposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

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Section: Nemo Structural Conundrummentioning

confidence: 99%

Section: Nemo Structural Conundrummentioning

confidence: 99%

Section: Nemo Structural Conundrummentioning

confidence: 99%

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Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

2010

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“…There are two known UBDs in NEMO, which consist of both structural classes of UBDs. The first is the ␣-helical UBAN (ubiquitin binding in ABIN and NEMO) domain, which has two known co-crystal structures with M1 and Lys-63-di-ubiquitin (14,15). Abolishing the ubiquitin binding function of the UBAN domain via point mutations has been shown to severely attenuate NF-B activation (14, 16 -18).…”

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confidence: 99%

Covalent Modification of the NF-κB Essential Modulator (NEMO) by a Chemical Compound Can Regulate Its Ubiquitin Binding Properties in Vitro

Hooper

Jackson

Coughlin

et al. 2014

Journal of Biological Chemistry

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Background: NEMO is a known ubiquitin-binding protein that functions as a key regulator of NF-B activation. Results: WA is able to covalently modify NEMO to induce a gain-of-function binding to long Lys-48-linked polyubiquitin chains. Conclusion: WA can change the NEMO specificity for polyubiquitin chain interaction. Significance: This study reveals a novel drug class to target the UBD:ubiquitin interaction.

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“…Like TAB2, NEMO can also bind to K63-linked chains and this binding event promotes IKK activation, again either through conformational changes induced by ubiquitin binding (Laplantine et al, 2009;Wu et al, 2006;Yoshikawa et al, 2009), by placing IKK in a context where it can be phosphorylated by upstream kinases such as TAK1, MEKK2 (MAPK/ERK kinase kinase 2, also known as MAP3K2) or MEKK3 (also known as MAP3K3) (Schmidt et al, 2003;Wang et al, 2001;Yang et al, 2001), or by inducing the clustering of IKK complexes and thereby favouring activation by transautophosphorylation (Hayden and Ghosh, 2008).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

No one can whistle a symphony alone – how different ubiquitin linkages cooperate to orchestrate NF-κB activity

Schmukle

Walczak

2012

Journal of Cell Science

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SummaryAlthough it has been known for a long time that ubiquitylation has a major role in the activation and regulation of the nuclear factor kappa B (NF-B) pathway, recent studies have revealed that the picture is a lot more complex than originally thought. NF-B and ubiquitylation initially became linked when it was recognised that lysine (K)48-linked ubiquitin chains are involved in the processing of NF-B precursors and the degradation of inhibitor of kappa B (IB) proteins. Soon thereafter, it was reported that K63-linked chains were involved in the assembly of IB kinase (IKK)-activating complexes and required for activation of the NF-B signalling pathway. Recently, the discovery that atypical ubiquitin linkages, including linear and K11 linkages, are also involved in the activation of NF-B has led to the need to re-evaluate existing models of how activation of this transcription factor is initiated and regulated. It is now becoming apparent that not only the canonical types of ubiquitin chains but possibly all linkage types have to be investigated in order to fully comprehend NF-B activation. This can be considered a turning point in our view of the regulation of one of the most important pathways of gene induction. Hence, in this Commentary, we summarise the information that is currently available and incorporate it into a new model of NF-B activation, thereby highlighting the emerging new challenges in understanding the role of ubiquitylation in NF-B activation.This article is part of a Minifocus on Ubiquitin. For further reading, please see related articles: ʻUbiquitin and SUMO in DNA repair at a glanceʼ by Helle D. Ulrich (J. Cell Sci. 125,(249)(250)(251)(252)(253)(254). ʻEmerging regulatory mechanisms in ubiquitin-dependent cell cycle controlʼ by Annamaria Mocciaro and Michael Rape (J. Cell Sci. 125, [255][256][257][258][259][260][261][262][263]. ʻThe role of ubiquitylation in receptor endocytosis and endosomal sortingʼ by Kaisa Haglund and Ivan Dikic (J. Cell Sci. 125,(265)(266)(267)(268)(269)(270)(271)(272)(273)(274)(275). ʻCellular functions of the DUBsʼ by Michael J. Clague et al. (J. Cell Sci. 125,[277][278][279][280][281][282][283][284][285][286]. ʻHECT and RING finger families of E3 ubiquitin ligases at a glanceʼ by Meredith B. Metzger et al. (J. Cell Sci. 125,(531)(532)(533)(534)(535)(536)(537). ʻNon-canonical ubiquitin-based signals for proteasomal degradationʼ by Yelena Kravtsova-Ivantsiv and Aaron Ciechanover (J. Cell Sci. 125, 539-548). Key words: NF-kappaB, Atypical linkage types, UbiquitinJournal of Cell Science atypical ubiquitin chains, such as linear and K11-linked chains (Dynek et al., 2010;Gerlach et al., 2011;Haas et al., 2009;Ikeda et al., 2011;Tokunaga et al., 2011;Tokunaga et al., 2009;Emmerich et al., 2011). In this Commentary, we discuss the effects of both the well-established, as well as these more recently discovered, ubiquitin chains on NF-B activation.The NF-B family of transcription factors The term NF-B refers not to a single protein but to a family of dimer...

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Crystal structure of the NEMO ubiquitin‐binding domain in complex with Lys 63‐linked di‐ubiquitin

Cited by 72 publications

References 26 publications

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

Covalent Modification of the NF-κB Essential Modulator (NEMO) by a Chemical Compound Can Regulate Its Ubiquitin Binding Properties in Vitro

No one can whistle a symphony alone – how different ubiquitin linkages cooperate to orchestrate NF-κB activity

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