O35613 (DAXX_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 114. History...
Names and origin
|Protein names||Recommended name:|
Death domain-associated protein 6
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||739 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 By similarity. Interacts with CBP; the interaction is dependent on the sumoylation of CBP and suppresses CBP transcriptional activity via recruitment of HDAC2. Ref.3
Homomultimer. Binds to the TNFRSF6 death domain via its C-terminus and to PAX5. Binds to SLC2A4/GLUT4, MAP3K5, TGFBR2, phosphorylated dimeric HSPB1/HSP27, CENPC, 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. 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 AXIN1; the interaction stimulates the interaction of DAXX with TP53, stimulates 'Ser-46' phosphorylation of TP53 on and induces cell death on UV irradiation. 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 By similarity. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7
Cytoplasm. Nucleus › nucleoplasm By similarity. Nucleus › PML body. Nucleus › nucleolus By similarity. 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 By similarity. Ref.3
The Sumo interaction motif mediates Sumo binding, and is required both for sumoylation and binding to sumoylated targets By similarity.
Sumoylated with SUMO1 on multiple lysine residues By similarity.
Repressor activity is down-regulated upon Ser-669 phosphorylation.
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 By similarity.
Belongs to the DAXX family.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 739||739||Death domain-associated protein 6||PRO_0000151259|
|Region||1 – 166||166||Necessary for interaction with USP7 By similarity|
|Region||353 – 576||224||Necessary for interaction with USP7 By similarity|
|Region||626 – 739||114||Interaction with SPOP By similarity|
|Region||732 – 739||8||Sumo interaction motif (SIM) By similarity|
|Coiled coil||185 – 223||39||Potential|
|Coiled coil||364 – 403||40||Potential|
|Coiled coil||445 – 488||44||Potential|
|Motif||391 – 395||5||Nuclear localization signal Potential|
|Motif||622 – 628||7||Nuclear localization signal Potential|
|Compositional bias||11 – 16||6||Poly-Asp|
|Compositional bias||442 – 501||60||Asp/Glu-rich (acidic)|
Amino acid modifications
|Modified residue||219||1||Phosphoserine Ref.6|
|Modified residue||472||1||Phosphothreonine Ref.6|
|Modified residue||502||1||Phosphoserine Ref.6|
|Modified residue||515||1||Phosphoserine Ref.6|
|Modified residue||523||1||Phosphothreonine Ref.6|
|Modified residue||626||1||Phosphoserine Ref.6|
|Modified residue||669||1||Phosphoserine; by HIPK1 Ref.6|
|Modified residue||687||1||Phosphoserine By similarity|
|Modified residue||701||1||Phosphoserine By similarity|
|Modified residue||736||1||Phosphoserine By similarity|
|Modified residue||738||1||Phosphoserine By similarity|
|Cross-link||630||Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO1) By similarity|
|Mutagenesis||502||1||S → A: No effect on phosphorylation by HIPK1. Ref.6|
|Mutagenesis||669||1||S → A: Diminishes phosphorylation by HIPK1. Ref.6|
|Sequence conflict||416||1||Q → K in AAC97971. Ref.2|
|Sequence conflict||452||1||D → DD in AAC97971. Ref.2|
|Sequence conflict||589||1||P → S in AAC97971. Ref.2|
|||"Daxx, a novel Fas-binding protein that activates JNK and apoptosis."|
Yang X., Khosravi-Far R., Chang H.Y., Baltimore D.
Cell 89:1067-1076(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Sequence of the mouse major histocompatibility complex class II region."|
Rowen L., Qin S., Madan A., Loretz C., James R., Dors M., Mix L., Hall J., Lasky S., Hood L.
Submitted (OCT-1998) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis."|
Zhong S., Salomoni P., Ronchetti S., Guo A., Ruggero D., Pandolfi P.P.
J. Exp. Med. 191:631-640(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PML.
|||"FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits Fas-mediated Jun NH2-terminal kinase activation."|
Rochat-Steiner V., Becker K., Micheau O., Schneider P., Burns K., Tschopp J.
J. Exp. Med. 192:1165-1174(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIPK3.
|||"The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells."|
Emelyanov A.V., Kovac C.R., Sepulveda M.A., Birshtein B.K.
J. Biol. Chem. 277:11156-11164(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PAX5.
|||"Homeodomain-interacting protein kinase 1 modulates Daxx localization, phosphorylation, and transcriptional activity."|
Ecsedy J.A., Michaelson J.S., Leder P.
Mol. Cell. Biol. 23:950-960(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HIPK1, MUTAGENESIS OF SER-502 AND SER-669, PHOSPHORYLATION AT SER-219; THR-472; SER-502; SER-515; THR-523; SER-626 AND SER-669, IDENTIFICATION BY MASS SPECTROMETRY.
|||"SUMO modification negatively modulates the transcriptional activity of CREB-binding protein via the recruitment of Daxx."|
Kuo H.-Y., Chang C.-C., Jeng J.-C., Hu H.-M., Lin D.-Y., Maul G.G., Kwok R.P.S., Shih H.-M.
Proc. Natl. Acad. Sci. U.S.A. 102:16973-16978(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CBP.
|+||Additional computationally mapped references.|
|AF006040 mRNA. Translation: AAC53284.1.|
AF110520 Genomic DNA. Translation: AAC97971.1.
AF100956 Genomic DNA. Translation: AAC69891.1.
|RefSeq||NP_001186662.1. NM_001199733.1. |
3D structure databases
|SMR||O35613. Positions 62-150, 188-392. |
Protein-protein interaction databases
|BioGrid||199054. 12 interactions.|
|IntAct||O35613. 14 interactions.|
Protocols and materials databases
Genome annotation databases
|MGI||MGI:1197015. Daxx. |
Gene expression databases
Family and domain databases
|InterPro||IPR005012. Daxx. |
|PANTHER||PTHR12766. PTHR12766. 1 hit. |
|Pfam||PF03344. Daxx. 1 hit. |
|Accession||Primary (citable) accession number: O35613|
Secondary accession number(s): Q9QWT8, Q9QWV3
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|