5lrx

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Structure of A20 OTU domain bound to ubiquitinStructure of A20 OTU domain bound to ubiquitin

Structural highlights

5lrx is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.85Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The post-translational modification of proteins with polyubiquitin regulates virtually all aspects of cell biology. Eight distinct chain linkage types co-exist in polyubiquitin and are independently regulated in cells. This 'ubiquitin code' determines the fate of the modified protein. Deubiquitinating enzymes of the ovarian tumour (OTU) family regulate cellular signalling by targeting distinct linkage types within polyubiquitin, and understanding their mechanisms of linkage specificity gives fundamental insights into the ubiquitin system. Here we reveal how the deubiquitinase Cezanne (also known as OTUD7B) specifically targets Lys11-linked polyubiquitin. Crystal structures of Cezanne alone and in complex with monoubiquitin and Lys11-linked diubiquitin, in combination with hydrogen-deuterium exchange mass spectrometry, enable us to reconstruct the enzymatic cycle in great detail. An intricate mechanism of ubiquitin-assisted conformational changes activates the enzyme, and while all chain types interact with the enzymatic S1 site, only Lys11-linked chains can bind productively across the active site and stimulate catalytic turnover. Our work highlights the plasticity of deubiquitinases and indicates that new conformational states can occur when a true substrate, such as diubiquitin, is bound at the active site.

Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne.,Mevissen TE, Kulathu Y, Mulder MP, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BD, Akutsu M, El Oualid F, Kawasaki M, Freund SM, Ovaa H, Komander D Nature. 2016 Oct 12;538(7625):402-405. doi: 10.1038/nature19836. PMID:27732584[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ Mevissen TE, Kulathu Y, Mulder MP, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BD, Akutsu M, El Oualid F, Kawasaki M, Freund SM, Ovaa H, Komander D. Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. Nature. 2016 Oct 12;538(7625):402-405. doi: 10.1038/nature19836. PMID:27732584 doi:http://dx.doi.org/10.1038/nature19836

5lrx, resolution 2.85Å

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