| General information | | DisProt: | DP00707 | | Name: | Death domain-associated protein 6 | | Synonym(s): | DAXX_HUMAN
Daxx
ETS1-associated protein 1
Fas death domain-associated protein
| | First appeared in release: | Release 5.7 (02/28/2011) | | UniProt: | Q9UER7 | | UniGene: | | | SwissProt: | DAXX_HUMAN | | TrEMBL: | | | NCBI (GI): | | | Source organism: | Homo sapiens (Human) | | Sequence length: | 740 | | Percent disordered: | 7% | | Homologues: | |
| Native sequence |
10 20 30 40 50 60
| | | | | |
MATANSIIVL DDDDEDEAAA QPGPSHPLPN AASPGAEAPS SSEPHGARGS SSSGGKKCYK - 60
LENEKLFEEF LELCKMQTAD HPEVVPFLYN RQQRAHSLFL ASAEFCNILS RVLSRARSRP - 120
AKLYVYINEL CTVLKAHSAK KKLNLAPAAT TSNEPSGNNP PTHLSLDPTN AENTASQSPR - 180
TRGSRRQIQR LEQLLALYVA EIRRLQEKEL DLSELDDPDS AYLQEARLKR KLIRLFGRLC - 240
ELKDCSSLTG RVIEQRIPYR GTRYPEVNRR IERLINKPGP DTFPDYGDVL RAVEKAAARH - 300
SLGLPRQQLQ LMAQDAFRDV GIRLQERRHL DLIYNFGCHL TDDYRPGVDP ALSDPVLARR - 360
LRENRSLAMS RLDEVISKYA MLQDKSEEGE RKKRRARLQG TSSHSADTPE ASLDSGEGPS - 420
GMASQGCPSA SRAETDDEDD EESDEEEEEE EEEEEEEATD SEEEEDLEQM QEGQEDDEEE - 480
DEEEEAAAGK DGDKSPMSSL QISNEKNLEP GKQISRSSGE QQNKGRIVSP SLLSEEPLAP - 540
SSIDAESNGE QPEELTLEEE SPVSQLFELE IEALPLDTPS SVETDISSSR KQSEEPFTTV - 600
LENGAGMVSS TSFNGGVSPH NWGDSGPPCK KSRKEKKQTG SGPLGNSYVE RQRSVHEKNG - 660
KKICTLPSPP SPLASLAPVA DSSTRVDSPS HGLVTSSLCI PSPARLSQTP HSQPPRPGTC - 720
KTSVATQCDP EEIIVLSDSD
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| Functional narrative |
Function: 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.
SUBUNIT: Homomultimer. Binds to the TNFRSF6 death domain via its C-terminus and to PAX5. Binds to SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC1, ETS1, sumoylated PML, UBE2I and MCRS1. Is part of a complex containing PAX5 and CREBBP. Interacts with HIPK2 and HIPK3 via its N-terminus. Interacts with HIPK1, which induces translocation from PML/POD/ND10 nuclear bodies to chromatin and enhances association with HDAC1 (By similarity). The non-phosphorylated form binds to PAX3, PAX7, DEK, HDAC1, HDAC2, HDAC3, acetylated histone H4 and histones H2A, H2B, H3 and H4. Interacts with SPOP. Part of a complex consisting of DAXX, CUL3 and SPOP. Interacts with CBP; the interaction is dependent the sumoylation of CBP and suppresses CBP transcriptional activity via recruitment of HDAC2 directly in the complex with TP53 and HIPK2. Interacts with AXIN1; the interaction stimulates the interaction of DAXX with TP53, stimulates \'Ser-46\' phosphorylation of TP53 on and induces cell death on UV irradiation. Interacts with HCMV tegument phosphoprotein pp71. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts (via N-terminus) with RASSF1 (via C-terminus); the interaction is independent of MDM2 and TP53. Interacts with MDM2; the interaction is direct. Interacts with USP7; the interaction is direct and independent of MDM2 and TP53. Interacts with TP53. P03243:- (xeno); NbExp=1; IntAct=EBI-77321, EBI-1561361; P10275:AR; NbExp=2; IntAct=EBI-77321, EBI-608057; P46100:ATRX; NbExp=1; IntAct=EBI-77321, EBI-396461; Q8N726:CDKN2A; NbExp=3; IntAct=EBI-77321, EBI-625922; Q92793:CREBBP; NbExp=1; IntAct=EBI-77321, EBI-81215; O43293:DAPK3; NbExp=1; IntAct=EBI-77321, EBI-77293; P03244:E1B (xeno); NbExp=3; IntAct=EBI-77321, EBI-1561155; P25445:FAS; NbExp=2; IntAct=EBI-77321, EBI-494743; P25446:Fas (xeno); NbExp=4; IntAct=EBI-77321, EBI-296206; Q13547:HDAC1; NbExp=1; IntAct=EBI-77321, EBI-301834; Q92769:HDAC2; NbExp=1; IntAct=EBI-77321, EBI-301821; Q86Z02:HIPK1; NbExp=1; IntAct=EBI-77321, EBI-692891; O88904:Hipk1 (xeno); NbExp=1; IntAct=EBI-77321, EBI-692945; P04792:HSPB1; NbExp=1; IntAct=EBI-77321, EBI-352682; P15991:HSPB1 (xeno); NbExp=2; IntAct=EBI-77321, EBI-1559114; Q99683:MAP3K5; NbExp=4; IntAct=EBI-77321, EBI-476263; Q96EZ8:MCRS1; NbExp=2; IntAct=EBI-77321, EBI-348259; Q00987:MDM2; NbExp=4; IntAct=EBI-77321, EBI-389668; Q99497:PARK7; NbExp=1; IntAct=EBI-77321, EBI-1164361; Q02650:Pax5 (xeno); NbExp=2; IntAct=EBI-77321, EBI-296260; P29590:PML; NbExp=1; IntAct=EBI-77321, EBI-295890; P14672:SLC2A4; NbExp=3; IntAct=EBI-77321, EBI-367146; P40763:STAT3; NbExp=2; IntAct=EBI-77321, EBI-518675; P63165:SUMO1; NbExp=4; IntAct=EBI-77321, EBI-80140; Q9NQB0:TCF7L2; NbExp=3; IntAct=EBI-77321, EBI-924724; P37173:TGFBR2; NbExp=1; IntAct=EBI-77321, EBI-296151; P04637:TP53; NbExp=3; IntAct=EBI-77321, EBI-366083; Q99816:TSG101; NbExp=1; IntAct=EBI-77321, EBI-346882; Q93009:USP7; NbExp=4; IntAct=EBI-77321, EBI-302474;
Subcellular Location: Cytoplasm. Nucleus, nucleoplasm. Nucleus, PML body. Nucleus, nucleolus. Chromosome, centromere. Note=Dispersed throughout the nucleoplasm, in PML/POD/ND10 nuclear bodies, and in nucleoli. Colocalizes with a subset of interphase centromeres, but is absent from mitotic centromeres. Detected in cytoplasmic punctate structures. Translocates from the nucleus to the cytoplasm upon glucose deprivation or oxidative stress. Colocalizes with RASSF1 in the nucleus. Colocalizes with USP7 in nucleoplasma with accumulation in speckled structures. Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q9UER7-1; Sequence=Displayed; Name=2; IsoId=Q9UER7-2; Sequence=VSP_001270; Note=No experimental confirmation available;
TISSUE SPECIFICITY: Ubiquitous.
INDUCTION: Upon mitogenic stimulation by concanavalin-A.
PTM: Sumoylated.
PTM: Phosphorylated upon DNA damage, probably by ATM or ATR. Phosphorylated by HIPK1 upon glucose deprivation.
PTM: Polyubiquitinated; which is promoted by CUL3 and SPOP and results in proteasomal degradation. Ubiquitinated by MDM2; inducing its degradation. Deubiquitinated by USP7; leading to stabilize it.
SIMILARITY: Belongs to the DAXX family.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL=\'http://atlasgeneticsoncology.org//Genes/DAXXID40265ch6p21.html\';
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| Map of ordered and disordered regions |
Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.
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| Region 1 | | Type: | Disordered - Extended | | Name: | N-terminal domain | | Location: | 1 - 54 | | Length: | 54 | | Region sequence: |
MATANSIIVLDDDDEDEAAAQPGPSHPLPNAASPGAEAPSSSEPHGARGSSSSG | | Modification type: | Fragment
Native
| | PDB: | | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Molecular recognition effectors
| | Functional subclasses: | Flexible linkers/spacers
Protein-protein binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.5; )
| References:
- 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; 18(12): 1642-53. PubMed: 21134643
- 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; 24(3): 341-54. PubMed: 17081986
- Santiago A, Godsey AC, Hossain J, Zhao LY, Liao D. "Identification of two independent SUMO-interacting motifs in Daxx: evolutionary conservation from Drosophila to humans and their biochemical functions." Cell Cycle. 2009; 8(1): 76-87. PubMed: 19106612
| Comments:According to Escobar-Cabrera et al (2010), Lin et al (2006) and Santiago et al (2009), Region 1 contains a SUMO-interacting motif (SIM) at aa 1-17.
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| Region 2 | | Type: | Ordered | | Name: | DHB domain | | Location: | 55 - 144 | | Length: | 90 | | Region sequence: |
GKKCYKLENEKLFEEFLELCKMQTADHPEVVPFLYNRQQRAHSLFLASAEFCNILSRVLS
RARSRPAKLYVYINELCTVLKAHSAKKKLN | | Modification type: | Fragment
Native
| | PDB: | 2KZS:A, 2KZU:A | | Structural/functional type: | Function arises from the ordered state
| | Functional classes: | Molecular recognition effectors
| | Functional subclasses: | Protein-protein binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (298 K; pH: 6.5; D2O 5 %; DAXX55-144 fragment (or DAXX55-144/Rassf1C23-38w complex); DTT 10 mM; EDTA 0.1 mM; KCl 100 mM; potassium phosphate 10 mM)
| References:
- 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; 18(12): 1642-53. PubMed: 21134643
| Comments:Escobar-Cabrera et al (2010) have characterized this region as the DAXX Helical Bundle (DHB) domain, a highly dynamic bundle of four alpha-helices, plus one small alpha-helix that cross-links H1 and H2 with H4 and H5. Helix positions are as follows: H1, aa 60-77; H2, aa 84-93; H3 crossover helix, aa 97-100; H4, aa 103-118; H5, aa 123-136.
PDB structure 2KZS is the DAXX55-144 fragment, while PDB structure 2KZU is DAXX55-144 fragment in complex with Rassf1C23-38w fragment.
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| References |
- 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; 18(12): 1642-53. PubMed: 21134643
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| Comments |
AV 2-10-2011 (PubMed: 21134643)
Escobar-Cabrera et al (2010) structurally characterized the DAXX protein using human DAXX for aa 1-565 and murine (mouse) DAXX for aa 566-739. DAXX is represented in DisProt by entry DP00707 Human DAXX and entry DP00708 Mouse DAXX.
Escobar-Cabrera et al (2010) found DAXX to be an intrinsically disordered protein with regions of local structure. Their overall characterization of DAXX, combining both human and mouse is as follows: SIM-N (N-terminal SUMO-interacting motif) at aa 1-17; IDR (intrinsically disordered region) at aa 18-54; DHB (DAXX helical bundle) at aa 55-144; putative IDR at aa 145-179; putative helical region at aa 180-400; putative IDR at aa 401-433; putative acidic region at aa 434-485; putative IDR at aa 486-494; SPE (segment rich in Ser/Pro/Glu) at aa 495-596; IDR at aa 597-664; SPT (segment rich in Ser/Pro/Thr) at 665-723; SIM-C (C-terminal SUMO-interacting motif) at aa 724-end of protein (aa 739 for mouse, 740 for human).
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