Crystal Structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 Complexes: Affinity, Specificity, and Regulation

Zheng, Chao; Kabaleeswaran, Venkataraman; Wang, Yaya; Cheng, Genhong; Wu, Hao

doi:10.1016/j.molcel.2010.03.009

Cited by 169 publications

(215 citation statements)

References 44 publications

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“…Indeed, this would explain why WT and cIAP1 Ϫ/Ϫ CD8 T cells do not require the noncanonical NF-B pathway when 4-1BB costimulation is present, but TRAF1 Ϫ/Ϫ T cells do. Whereas the present study shows that TRAF1 is critical to prevent NIK activation in activated T cells, Zheng et al did not observe constitutive processing of p100 to p52 in TRAF1 Ϫ/Ϫ -resting B cells (47). As resting B cells, and in fact most nonlymphoid cells, lack detectable TRAF1 (58), the regulation of NIK in resting primary B cells and other cell types could not involve TRAF1 or these cells would show constitutive alternative NF-B activation.…”

Section: Discussioncontrasting

confidence: 81%

“…A recent study using an overexpression system, reported that TRAF1 and TRAF2 can be pulled down with TAP tagged NIK, suggesting that TRAF1 like TRAF2 might be part of the E3 complex for NIK (47). Here we have unconvered a hitherto unrecognized role for TRAF1 in contributing to inhibition of the non-canonical NF-B pathway in TCR-activated CD8 T cells.…”

Section: Discussionmentioning

confidence: 51%

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Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

McPherson

Snell

Mak

et al. 2012

Journal of Biological Chemistry

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Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 51%

Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

McPherson

Snell

Mak

et al. 2012

Journal of Biological Chemistry

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“…This suggests that upon TNF stimulation cIAP1 is recruited to receptor complexes by TRAF2, and cIAP1 dimerization is promoted. Recently, it has been shown that the TRAF2 trimer only binds to a single cIAP protein (51,52); therefore, cIAP dimer formation is likely to require the interaction of cIAP molecules bound to two TRAF2 trimers. Whether two separate TNFR1-TRADD complexes recruit two TRAF2 trimers or whether the cIAP RING dimer is sufficient to facilitate cIAP1/TRAF2 recruitment without the involvement of another receptor is an interesting question.…”

Section: Discussionmentioning

confidence: 99%

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization

Feltham

Bettjeman

Budhidarmo

et al. 2011

Journal of Biological Chemistry

146

152

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The inhibitor of apoptosis (IAP) proteins are important ubiquitin E3 ligases that regulate cell survival and oncogenesis. The cIAP1 and cIAP2 paralogs bear three N-terminal baculoviral IAP repeat (BIR) domains and a C-terminal E3 ligase RING domain. IAP antagonist compounds, also known as Smac mimetics, bind the BIR domains of IAPs and trigger rapid RING-dependent autoubiquitylation, but the mechanism is unknown. We show that RING dimerization is essential for the E3 ligase activity of cIAP1 and cIAP2 because monomeric RING mutants could not interact with the ubiquitin-charged E2 enzyme and were resistant to Smac mimetic-induced autoubiquitylation. Unexpectedly, the BIR domains inhibited cIAP1 RING dimerization, and cIAP1 existed predominantly as an inactive monomer. However, addition of either mono-or bivalent Smac mimetics relieved this inhibition, thereby allowing dimer formation and promoting E3 ligase activation. In contrast, the cIAP2 dimer was more stable, had higher intrinsic E3 ligase activity, and was not highly activated by Smac mimetics. These results explain how Smac mimetics promote rapid destruction of cIAP1 and suggest mechanisms for activating cIAP1 in other pathways.The attachment of ubiquitin and ubiquitin-like molecules to intracellular proteins is a key process that regulates many cellular events (1). A hierarchical multienzyme cascade brings about the attachment of ubiquitin to substrate proteins. Ubiquitin is first activated by the ubiquitin-activating enzyme (E1) and then is transferred to the active site cysteine of the ubiquitin-conjugating enzyme (E2). Subsequently, ubiquitin-protein ligases (E3s) promote the transfer of ubiquitin from the E2 to lysine residues in target proteins. The RING 4 domain-containing E3 ligases, which are prevalent in mammals (Ͼ300), do not directly interact with ubiquitin; instead, the RING domain binds to the E2 and promotes the transfer of ubiquitin from the E2ϳubiquitin (E2ϳUb) thioester conjugate to the target protein (2). The mechanism by which the RING domain promotes ubiquitin transfer is not obvious because the RING-binding site on the E2 is distant from the active site. It has been proposed that the RING domain simply brings the E2ϳUb conjugate into close proximity with the substrate and that the increased availability of E2s promotes transfer of ubiquitin to the substrate. However, interactions between RING domains and E2s are generally transient and have modest affinity, and tighter binding does not always correlate with increased activity. In addition, not all RING-E2 complexes promote transfer, demonstrating that proximity alone is insufficient (3). Notably, the RING domains of Brca1 and c-Cbl interact with UbcH7 and UbcH5b, but only interaction with UbcH5b results in ubiquitin transfer (3, 4). Others have suggested that an allosteric mechanism is important whereby interaction of the RING domain with the E2 leads to changes at its active site that promote release of ubiquitin (5, 6). Consistent with this, binding of the G2BR domain of the E3 gp78...

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“…[2][3][4][5] The E3 ubiquitin ligase TRAF2 was the first to be described as being responsible for K63 ubiquitination of RIP1 [5][6][7] together with the lipid shingosine-1-phosphate. 8 Other publications have shown that cIAP1/2 can attach K63 ubiquitin chains to RIP1 [9][10][11][12] or that TRAF2 and cIAPs cooperate for the ubiquitination of RIP1 6,13,14 . These ubiquitin chains bind and associate the TAB/TAK (TAK1/TAB2/TAB3) and NEMO/IKK (IKKa, b, g) kinases complex.…”

mentioning

confidence: 99%

De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

Pazarentzos

Datler

et al. 2011

Cell Death Differ

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Components of the TNFR1 complex are subject to dynamic ubiquitination that impacts on their effects as signalling factors. We have found that the ubiquitin-specific protease USP2a has a pivotal role in the decision for cell death or survival by the TNFR1 complex. This enzyme is a novel component of the TNFR1 complex that is recruited upon ligand binding and controls the signalling activity of the TNFR1-interacting protein RIP1 by removing its K63-linked ubiquitin chains. USP2a similarly de-ubiquitinates TRAF2, a ubiquitin-ligase recruited to the TNFR1 complex. During the TNF response the activity of USP2a on RIP1 and TRAF2 is required for the efficient reappearance of IjBa, which is essential to inactivate the anti-apoptotic transcription factor NF-jB. The effects of USP2a culminate in the conversion of the anti-apoptotic TNFR1 complex I into the pro-apoptotic TNFR1 complex II. Consequently, downregulation of USP2a promotes NF-jB activation and protects cells against TNF-induced cell death. Tumour necrosis factor (TNF) is a pleiotropic cytokine that can, through the TNF receptor 1 (TNFR1), elicit various cellular responses ranging from inflammation, cell proliferation, cell survival to apoptosis. The interaction of this cytokine with TNFR1 results in the recruitment of the adaptor TRADD to its intracellular death domain. RIP kinase 1 (RIP1), the ubiquitin ligase TNF receptor-associated factor 2 (TRAF2), and the inhibitors of apoptosis cIAP1 and cIAP2 then associate in the so-called complex I. 1 Following its recruitment to the complex I, RIP1 is ubiquitinated mainly by K63 ubiquitin chains. 2-5 The E3 ubiquitin ligase TRAF2 was the first to be described as being responsible for K63 ubiquitination of RIP1 5-7 together with the lipid shingosine-1-phosphate. 8 Other publications have shown that cIAP1/2 can attach K63 ubiquitin chains to RIP1 [9][10][11][12] or that TRAF2 and cIAPs cooperate for the ubiquitination of RIP1 6,13,14 . These ubiquitin chains bind and associate the TAB/TAK (TAK1/TAB2/TAB3) and NEMO/IKK (IKKa, b, g) kinases complex. 3,4,12,15 By proximity, TAK1 activates IKKb by phosphorylation, which in turn phosphorylates IkBa to promote its K48-linked polyubiquitination and degradation by the proteasome. The antiapoptotic transcription factor NF-kB is then free to translocate to the nucleus and activate gene transcription leading to survival of the cells. 7,[15][16][17][18][19][20] Upon internalisation of the complex and in the absence of K63 ubiquitination, RIP1 is able to form the so-called complex II with FADD and pro-caspase-8 to initiate apoptosis. 1,16 Hence, ubiquitin conjugation has a crucial role in allowing cells to decide between cell death and survival in the TNF signalling cascade. Although a number of ubiquitin ligases, that presumably modify components of the TNFR1 complex, have been identified, so far only two de-ubiquitinating proteases have functionally been found in the TNF signalling pathway that impact on cell death, A20 and CYLD (cylindromatosis tumour suppressor). 21-24 A20 is a ...

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Crystal Structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 Complexes: Affinity, Specificity, and Regulation

Cited by 169 publications

References 44 publications

Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

Smac Mimetics Activate the E3 Ligase Activity of cIAP1 Protein by Promoting RING Domain Dimerization

De-ubiquitinating protease USP2a targets RIP1 and TRAF2 to mediate cell death by TNF

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