View source for 2xxn


==Structure of the vIRF4-HAUSP TRAF domain complex==
<StructureSection load='2xxn' size='340' side='right'caption='[[2xxn]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2xxn]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_gammaherpesvirus_8 Human gammaherpesvirus 8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2XXN FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</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=2xxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xxn OCA], [https://pdbe.org/2xxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2xxn RCSB], [https://www.ebi.ac.uk/pdbsum/2xxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2xxn ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/UBP7_HUMAN UBP7_HUMAN] Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX. Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Exhibits a preference towards 'Lys-48'-linked Ubiquitin chains.<ref>PMID:11923872</ref> <ref>PMID:14506283</ref> <ref>PMID:15053880</ref> <ref>PMID:16160161</ref> <ref>PMID:16964248</ref> <ref>PMID:18716620</ref> <ref>PMID:18590780</ref> <ref>PMID:20153724</ref> <ref>PMID:21745816</ref> <ref>PMID:22411829</ref> <ref>PMID:22689415</ref> <ref>PMID:22466611</ref> <ref>PMID:22466612</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Herpesvirus-associated ubiquitin-specific protease (HAUSP) regulates the stability of p53 and the p53-binding protein MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated antitumor activity. Here we report the structural analysis of HAUSP with Kaposi's sarcoma-associated herpesvirus viral interferon (IFN) regulatory factor 4 (vIRF4) and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction that results in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, whereas the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell-cycle arrest and apoptosis in culture and to tumor regression in xenograft mouse model. Thus, the virus has developed a unique strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists.

Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein.,Lee HR, Choi WC, Lee S, Hwang J, Hwang E, Guchhait K, Haas J, Toth Z, Jeon YH, Oh TK, Kim MH, Jung JU Nat Struct Mol Biol. 2011 Nov 6;18(12):1336-44. doi: 10.1038/nsmb.2142. PMID:22056774<ref>PMID:22056774</ref>

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

==See Also==
*[[Thioesterase 3D structures|Thioesterase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Human gammaherpesvirus 8]]
[[Category: Large Structures]]
[[Category: Choi WC]]
[[Category: Hwang J]]
[[Category: Kim MH]]