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- | [[Image:3brv.jpg|left|200px]] | |
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- | <!--
| + | ==NEMO/IKKb association domain structure== |
- | The line below this paragraph, containing "STRUCTURE_3brv", creates the "Structure Box" on the page.
| + | <StructureSection load='3brv' size='340' side='right'caption='[[3brv]], [[Resolution|resolution]] 2.20Å' scene=''> |
- | You may change the PDB parameter (which sets the PDB file loaded into the applet)
| + | == Structural highlights == |
- | or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
| + | <table><tr><td colspan='2'>[[3brv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BRV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BRV FirstGlance]. <br> |
- | or leave the SCENE parameter empty for the default display.
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
- | -->
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3brv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3brv OCA], [https://pdbe.org/3brv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3brv RCSB], [https://www.ebi.ac.uk/pdbsum/3brv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3brv ProSAT]</span></td></tr> |
- | {{STRUCTURE_3brv| PDB=3brv | SCENE= }}
| + | </table> |
- | | + | == Function == |
- | '''NEMO/IKKb association domain structure'''
| + | [https://www.uniprot.org/uniprot/IKKB_HUMAN IKKB_HUMAN] Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.<ref>PMID:11297557</ref> <ref>PMID:17213322</ref> <ref>PMID:20434986</ref> <ref>PMID:20410276</ref> <ref>PMID:20797629</ref> <ref>PMID:21138416</ref> |
- | | + | == Evolutionary Conservation == |
- | | + | [[Image:Consurf_key_small.gif|200px|right]] |
- | ==Overview== | + | Check<jmol> |
- | The phosphorylation of IkappaB by the IKK complex targets it for degradation and releases NF-kappaB for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKKalpha/beta kinases and a regulatory protein, NF-kappaB essential modulator (NEMO; IKKgamma). NEMO associates with the unphosphorylated IKK kinase C termini and activates the IKK complex's catalytic activity. However, detailed structural information about the NEMO/IKK interaction is lacking. In this study, we have identified the minimal requirements for NEMO and IKK kinase association using a variety of biophysical techniques and have solved two crystal structures of the minimal NEMO/IKK kinase associating domains. We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent.
| + | <jmolCheckbox> |
- | | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/br/3brv_consurf.spt"</scriptWhenChecked> |
- | ==About this Structure== | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
- | 3BRV is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BRV OCA].
| + | <text>to colour the structure by Evolutionary Conservation</text> |
- | | + | </jmolCheckbox> |
- | ==Reference== | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3brv ConSurf]. |
- | Structure of a NEMO/IKK-Associating Domain Reveals Architecture of the Interaction Site., Rushe M, Silvian L, Bixler S, Chen LL, Cheung A, Bowes S, Cuervo H, Berkowitz S, Zheng T, Guckian K, Pellegrini M, Lugovskoy A, Structure. 2008 May;16(5):798-808. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18462684 18462684]
| + | <div style="clear:both"></div> |
| + | == References == |
| + | <references/> |
| + | __TOC__ |
| + | </StructureSection> |
| [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
- | [[Category: I-kappa-B kinase]] | + | [[Category: Large Structures]] |
- | [[Category: Protein complex]]
| + | [[Category: Silvian LF]] |
- | [[Category: Silvian, L F.]] | + | |
- | [[Category: Acetylation]]
| + | |
- | [[Category: Atp-binding]]
| + | |
- | [[Category: Coiled coil]]
| + | |
- | [[Category: Cytoplasm]]
| + | |
- | [[Category: Disease mutation]]
| + | |
- | [[Category: Ectodermal dysplasia]]
| + | |
- | [[Category: Fip3]]
| + | |
- | [[Category: Host-virus interaction]]
| + | |
- | [[Category: Ikk-gamma]]
| + | |
- | [[Category: Ikkap1]]
| + | |
- | [[Category: Kinase]]
| + | |
- | [[Category: Nemo]]
| + | |
- | [[Category: Nf-kb essential modulator]]
| + | |
- | [[Category: Nucleotide-binding]]
| + | |
- | [[Category: Nucleus]]
| + | |
- | [[Category: Phosphoprotein]]
| + | |
- | [[Category: Polymorphism]]
| + | |
- | [[Category: Serine/threonine-protein kinase]]
| + | |
- | [[Category: Transcription]]
| + | |
- | [[Category: Transcription regulation]]
| + | |
- | [[Category: Transferase]]
| + | |
- | [[Category: Transferase/transcription complex]]
| + | |
- | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu May 22 22:35:37 2008''
| + | |
| Structural highlights
Function
IKKB_HUMAN Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.[1] [2] [3] [4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Salmeron A, Janzen J, Soneji Y, Bump N, Kamens J, Allen H, Ley SC. Direct phosphorylation of NF-kappaB1 p105 by the IkappaB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem. 2001 Jun 22;276(25):22215-22. Epub 2001 Apr 10. PMID:11297557 doi:10.1074/jbc.M101754200
- ↑ Lobry C, Lopez T, Israel A, Weil R. Negative feedback loop in T cell activation through IkappaB kinase-induced phosphorylation and degradation of Bcl10. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):908-13. Epub 2007 Jan 9. PMID:17213322 doi:10.1073/pnas.0606982104
- ↑ Cui J, Zhu L, Xia X, Wang HY, Legras X, Hong J, Ji J, Shen P, Zheng S, Chen ZJ, Wang RF. NLRC5 negatively regulates the NF-kappaB and type I interferon signaling pathways. Cell. 2010 Apr 30;141(3):483-96. doi: 10.1016/j.cell.2010.03.040. PMID:20434986 doi:10.1016/j.cell.2010.03.040
- ↑ Yoboua F, Martel A, Duval A, Mukawera E, Grandvaux N. Respiratory syncytial virus-mediated NF-kappa B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKK beta. J Virol. 2010 Jul;84(14):7267-77. doi: 10.1128/JVI.00142-10. Epub 2010 Apr 21. PMID:20410276 doi:10.1128/JVI.00142-10
- ↑ Tsuchiya Y, Asano T, Nakayama K, Kato T Jr, Karin M, Kamata H. Nuclear IKKbeta is an adaptor protein for IkappaBalpha ubiquitination and degradation in UV-induced NF-kappaB activation. Mol Cell. 2010 Aug 27;39(4):570-82. doi: 10.1016/j.molcel.2010.07.030. PMID:20797629 doi:10.1016/j.molcel.2010.07.030
- ↑ Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P. Novel cross-talk within the IKK family controls innate immunity. Biochem J. 2011 Feb 15;434(1):93-104. doi: 10.1042/BJ20101701. PMID:21138416 doi:10.1042/BJ20101701
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