View source for 2jo9


==Mouse Itch 3rd WW domain complex with the Epstein-Barr virus latent membrane protein 2A derived peptide EEPPPPYED==
<StructureSection load='2jo9' size='340' side='right'caption='[[2jo9]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2jo9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human_herpesvirus_4_strain_B95-8 Human herpesvirus 4 strain B95-8] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JO9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JO9 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=2jo9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2jo9 OCA], [https://pdbe.org/2jo9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2jo9 RCSB], [https://www.ebi.ac.uk/pdbsum/2jo9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2jo9 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ITCH_MOUSE ITCH_MOUSE] Note=Defects in Itch are the cause of the itchy phenotype which is an inflammatory and immunological condition characterized by inflammation in the lung and stomach, hyperplasia in lymphoid and hematopoietic cells and constant itching in the skin.<ref>PMID:9462742</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ITCH_MOUSE ITCH_MOUSE] Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 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 NFKB1 (By similarity). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (By similarity). Regulates the transcriptional activity of several transcription factors involved in immune response. Critical regulator of T-helper (TH2) cytokine development through its ability to induce JUNB ubiquitination and degradation. Ubiquitinates SNX9 (By similarity). Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway (By similarity). It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (By similarity). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (By similarity).<ref>PMID:11828324</ref> <ref>PMID:15358865</ref> <ref>PMID:17592138</ref> <ref>PMID:18628966</ref> <ref>PMID:20392206</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jo/2jo9_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=2jo9 ConSurf].
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== Publication Abstract from PubMed ==
In this work, we study the role of phosphorylation as a regulatory mechanism for the interaction between the E3 ubiquitin ligase ItchWW3 domain and two PPxY motifs of one of its targets, the Epstein-Barr virus latent membrane protein 2A. Whereas ligand phosphorylation only diminishes binding, domain phosphorylation at residue T30 abrogates it. We show that two ItchWW domains can be phosphorylated at this position, using CK2 and PKA kinases and/or with stimulated T lymphocyte lysates. To better understand the regulation process, we determined the NMR structures of the ItchWW3-PPxY complex and of the phosphoT30-ItchWW3 variant. The peptide binds the domain using both XP and tyrosine grooves. A hydrogen bond from T30 to the ligand is also detected. This hydrogen-bond formation is precluded in the variant, explaining the inhibition upon phosphorylation. Our results suggest that phosphorylation at position 30 in ItchWW domains can be a mechanism to inhibit target recognition in vivo.

NMR structural studies of the ItchWW3 domain reveal that phosphorylation at T30 inhibits the interaction with PPxY-containing ligands.,Morales B, Ramirez-Espain X, Shaw AZ, Martin-Malpartida P, Yraola F, Sanchez-Tillo E, Farrera C, Celada A, Royo M, Macias MJ Structure. 2007 Apr;15(4):473-83. PMID:17437719<ref>PMID:17437719</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 2jo9" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human herpesvirus 4 strain B95-8]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Macias MJ]]
[[Category: Martin-Malpartida P]]
[[Category: Morales B]]
[[Category: Ramirez-Espain X]]
[[Category: Royo M]]
[[Category: Ruiz L]]
[[Category: Shaw AZ]]
[[Category: Yraola F]]