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==DAXX helical bundle (DHB) domain / Rassf1C complex==
==DAXX helical bundle (DHB) domain / Rassf1C complex==
<StructureSection load='2kzu' size='340' side='right' caption='[[2kzu]], [[NMR_Ensembles_of_Models | 25 NMR models]]' scene=''>
<StructureSection load='2kzu' size='340' side='right'caption='[[2kzu]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2kzu]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KZU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2KZU FirstGlance]. <br>
<table><tr><td colspan='2'>[[2kzu]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2KZU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2KZU FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2kzs|2kzs]]</td></tr>
</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DAXX, DADB-159G18.9-007, DAMC-227D19.15-007, DAQB-126H3.2-007, XXbac-BCX165D10.3-007, XXbac-BPG185D15.6-007 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RASSF1, hCG_17462 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2kzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kzu OCA], [https://pdbe.org/2kzu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2kzu RCSB], [https://www.ebi.ac.uk/pdbsum/2kzu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2kzu ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2kzu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2kzu OCA], [http://pdbe.org/2kzu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2kzu RCSB], [http://www.ebi.ac.uk/pdbsum/2kzu PDBsum]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/RASF1_HUMAN RASF1_HUMAN]] Potential tumor suppressor. Required for death receptor-dependent apoptosis. Mediates activation of STK3/MST2 and STK4/MST1 during Fas-induced apoptosis by preventing their dephosphorylation. When associated with MOAP1, promotes BAX conformational change and translocation to mitochondrial membranes in response to TNF and TNFSF10 stimulation. Isoform A interacts with CDC20, an activator of the anaphase-promoting complex, APC, resulting in the inhibition of APC activity and mitotic progression. Inhibits proliferation by negatively regulating cell cycle progression at the level of G1/S-phase transition by regulating accumulation of cyclin D1 protein. Isoform C has been shown not to perform these roles, no function has been identified for this isoform. Isoform A disrupts interactions among MDM2, DAXX and USP7, thus contributing to the efficient activation of TP53 by promoting MDM2 self-ubiquitination in cell-cycle checkpoint control in response to DNA damage.<ref>PMID:10888881</ref> <ref>PMID:11333291</ref> <ref>PMID:12024041</ref> <ref>PMID:14743218</ref> <ref>PMID:15109305</ref> <ref>PMID:15949439</ref> <ref>PMID:16510573</ref> <ref>PMID:18566590</ref> <ref>PMID:21199877</ref>
[https://www.uniprot.org/uniprot/DAXX_HUMAN DAXX_HUMAN] Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Proposed to mediate activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Down-regulates basal and activated transcription. Seems to act as a transcriptional corepressor and inhibits PAX3 and ETS1 through direct protein-protein interaction. Modulates PAX5 activity. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively.<ref>PMID:12140263</ref> <ref>PMID:15364927</ref> <ref>PMID:17081986</ref> <ref>PMID:16845383</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Death-associated protein|Death-associated protein]]
*[[Death-associated protein 3D structures|Death-associated protein 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Escobar-Cabrera, E]]
[[Category: Large Structures]]
[[Category: Giovinazzi, S]]
[[Category: Escobar-Cabrera E]]
[[Category: Ishov, A M]]
[[Category: Giovinazzi S]]
[[Category: Lau, D K.W]]
[[Category: Ishov AM]]
[[Category: McIntosh, L P]]
[[Category: Lau DKW]]
[[Category: Apoptosis]]
[[Category: McIntosh LP]]
[[Category: Daxx helical bundle domain]]
[[Category: Fas death-domain associated protein]]
[[Category: Ras-association domain family 1c protein]]
[[Category: Tumor suppressor]]

Latest revision as of 08:38, 15 May 2024

DAXX helical bundle (DHB) domain / Rassf1C complexDAXX helical bundle (DHB) domain / Rassf1C complex

Structural highlights

2kzu is a 2 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DAXX_HUMAN Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Proposed to mediate activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Down-regulates basal and activated transcription. Seems to act as a transcriptional corepressor and inhibits PAX3 and ETS1 through direct protein-protein interaction. Modulates PAX5 activity. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively.[1] [2] [3] [4]

Publication Abstract from PubMed

DAXX is a scaffold protein with diverse roles including transcription and cell cycle regulation. Using NMR spectroscopy, we demonstrate that the C-terminal half of DAXX is intrinsically disordered, whereas a folded domain is present near its N terminus. This domain forms a left-handed four-helix bundle (H1, H2, H4, H5). However, due to a crossover helix (H3), this topology differs from that of the Sin3 PAH domain, which to date has been used as a model for DAXX. The N-terminal residues of the tumor suppressor Rassf1C fold into an amphipathic alpha helix upon binding this DAXX domain via a shallow cleft along the flexible helices H2 and H5 (K(D) approximately 60 muM). Based on a proposed DAXX recognition motif as hydrophobic residues preceded by negatively charged groups, we found that peptide models of p53 and Mdm2 also bound the helical bundle. These data provide a structural foundation for understanding the diverse functions of DAXX.

Structural Characterization of the DAXX N-Terminal Helical Bundle Domain and Its Complex with Rassf1C.,Escobar-Cabrera E, Lau DK, Giovinazzi S, Ishov AM, McIntosh LP Structure. 2010 Dec 8;18(12):1642-53. PMID:21134643[5]

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

See Also

References

  1. ↑ Hollenbach AD, McPherson CJ, Mientjes EJ, Iyengar R, Grosveld G. Daxx and histone deacetylase II associate with chromatin through an interaction with core histones and the chromatin-associated protein Dek. J Cell Sci. 2002 Aug 15;115(Pt 16):3319-30. PMID:12140263
  2. ↑ Zhao LY, Liu J, Sidhu GS, Niu Y, Liu Y, Wang R, Liao D. Negative regulation of p53 functions by Daxx and the involvement of MDM2. J Biol Chem. 2004 Nov 26;279(48):50566-79. Epub 2004 Sep 10. PMID:15364927 doi:10.1074/jbc.M406743200
  3. ↑ Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, Ho CC, Chen YC, Lin TP, Fang HI, Hung CC, Suen CS, Hwang MJ, Chang KS, Maul GG, Shih HM. Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell. 2006 Nov 3;24(3):341-54. PMID:17081986 doi:10.1016/j.molcel.2006.10.019
  4. ↑ Tang J, Qu LK, Zhang J, Wang W, Michaelson JS, Degenhardt YY, El-Deiry WS, Yang X. Critical role for Daxx in regulating Mdm2. Nat Cell Biol. 2006 Aug;8(8):855-62. Epub 2006 Jul 16. PMID:16845383 doi:10.1038/ncb1442
  5. ↑ Escobar-Cabrera E, Lau DK, Giovinazzi S, Ishov AM, McIntosh LP. Structural Characterization of the DAXX N-Terminal Helical Bundle Domain and Its Complex with Rassf1C. Structure. 2010 Dec 8;18(12):1642-53. PMID:21134643 doi:10.1016/j.str.2010.09.016
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