| Structural highlights
Function
[TNAP3_HUMAN] Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate both 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The NF-kappaB (nuclear factor kappaB) regulator A20 antagonises IKK [IkappaB (inhibitor of kappaB) kinase] activation by modulating Lys63-linked polyubiquitination of cytokine-receptor-associated factors including TRAF2/6 (tumour-necrosis-factor-receptor-associated factor 2/6) and RIP1 (receptor-interacting protein 1). In the present paper we describe the crystal structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20, which differs from other deubiquitinases but shares the minimal catalytic core with otubain-2. Analysis of conserved surface regions allows prediction of ubiquitin-binding sites for the proximal and distal ubiquitin molecules. Structural and biochemical analysis suggests a novel architecture of the catalytic triad, which might be present in a subset of OTU domains including Cezanne and TRABID (TRAF-binding domain). Biochemical analysis shows a preference of the isolated A20 OTU domain for Lys48-linked tetraubiquitin in vitro suggesting that additional specificity factors might be required for the physiological function of A20 in cells.
Structure of the A20 OTU domain and mechanistic insights into deubiquitination.,Komander D, Barford D Biochem J. 2008 Jan 1;409(1):77-85. PMID:17961127[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6721-5. PMID:8692885
- ↑ De Valck D, Heyninck K, Van Criekinge W, Vandenabeele P, Fiers W, Beyaert R. A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins. Biochem Biophys Res Commun. 1997 Sep 18;238(2):590-4. PMID:9299557 doi:10.1006/bbrc.1997.7343
- ↑ Eliopoulos AG, Blake SM, Floettmann JE, Rowe M, Young LS. Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. J Virol. 1999 Feb;73(2):1023-35. PMID:9882303
- ↑ Evans PC, Ovaa H, Hamon M, Kilshaw PJ, Hamm S, Bauer S, Ploegh HL, Smith TS. Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity. Biochem J. 2004 Mar 15;378(Pt 3):727-34. PMID:14748687 doi:10.1042/BJ20031377
- ↑ Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature. 2004 Aug 5;430(7000):694-9. Epub 2004 Jul 18. PMID:15258597 doi:10.1038/nature02794
- ↑ Mauro C, Pacifico F, Lavorgna A, Mellone S, Iannetti A, Acquaviva R, Formisano S, Vito P, Leonardi A. ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem. 2006 Jul 7;281(27):18482-8. Epub 2006 May 9. PMID:16684768 doi:10.1074/jbc.M601502200
- ↑ Li L, Soetandyo N, Wang Q, Ye Y. The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation. Biochim Biophys Acta. 2009 Feb;1793(2):346-53. doi: 10.1016/j.bbamcr.2008.09.013., Epub 2008 Oct 8. PMID:18952128 doi:10.1016/j.bbamcr.2008.09.013
- ↑ Duwel M, Welteke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, Darnay BG, Ruland J, Marynen P, Krappmann D. A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. J Immunol. 2009 Jun 15;182(12):7718-28. doi: 10.4049/jimmunol.0803313. PMID:19494296 doi:10.4049/jimmunol.0803313
- ↑ Skaug B, Chen J, Du F, He J, Ma A, Chen ZJ. Direct, noncatalytic mechanism of IKK inhibition by A20. Mol Cell. 2011 Nov 18;44(4):559-71. doi: 10.1016/j.molcel.2011.09.015. PMID:22099304 doi:10.1016/j.molcel.2011.09.015
- ↑ Komander D, Barford D. Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochem J. 2008 Jan 1;409(1):77-85. PMID:17961127 doi:10.1042/BJ20071399
- ↑ Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, Darnay BG, Wu H. Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20. J Mol Biol. 2008 Feb 15;376(2):526-40. Epub 2007 Dec 4. PMID:18164316 doi:http://dx.doi.org/10.1016/j.jmb.2007.11.092
- ↑ Komander D, Barford D. Structure of the A20 OTU domain and mechanistic insights into deubiquitination. Biochem J. 2008 Jan 1;409(1):77-85. PMID:17961127 doi:10.1042/BJ20071399
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