ID MDM4_HUMAN Reviewed; 490 AA.
AC O15151; Q2M2Y2; Q32SL2; Q6GS18; Q8IV83;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 27-SEP-2005, sequence version 2.
DT 24-JAN-2024, entry version 221.
DE RecName: Full=Protein Mdm4;
DE AltName: Full=Double minute 4 protein;
DE AltName: Full=Mdm2-like p53-binding protein;
DE AltName: Full=Protein Mdmx;
DE AltName: Full=p53-binding protein Mdm4;
GN Name=MDM4; Synonyms=MDMX;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Colon tumor;
RX PubMed=9226370; DOI=10.1006/geno.1997.4775;
RA Shvarts A., Bazuine M., Dekker P., Ramos Y.F.M., Steegenga W.T., Merckx G.,
RA van Ham R.C.A., van der Houven van Oordt W., van der Eb A.J.,
RA Jochemsen A.G.;
RT "Isolation and identification of the human homolog of a new p53-binding
RT protein, Mdmx.";
RL Genomics 43:34-42(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM HDMX211).
RX PubMed=16266988; DOI=10.1158/0008-5472.can-05-0450;
RA Giglio S., Mancini F., Gentiletti F., Sparaco G., Felicioni L., Barassi F.,
RA Martella C., Prodosmo A., Iacovelli S., Buttitta F., Farsetti A., Soddu S.,
RA Marchetti A., Sacchi A., Pontecorvi A., Moretti F.;
RT "Identification of an aberrantly spliced form of HDMX in human tumors: a
RT new mechanism for HDM2 stabilization.";
RL Cancer Res. 65:9687-9694(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Gastric mucosa;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-175 AND ILE-406.
RG NIEHS SNPs program;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 5).
RC TISSUE=Brain, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP ALTERNATIVE SPLICING (ISOFORMS 2 AND 3).
RX PubMed=12761890; DOI=10.1002/jcb.10535;
RA Rallapalli R., Strachan G., Tuan R.S., Hall D.J.;
RT "Identification of a domain within MDMX-S that is responsible for its high
RT affinity interaction with p53 and high-level expression in mammalian
RT cells.";
RL J. Cell. Biochem. 89:563-575(2003).
RN [8]
RP MUTAGENESIS OF CYS-437.
RX PubMed=10608892; DOI=10.1074/jbc.274.53.38189;
RA Sharp D.A., Kratowicz S.A., Sank M.J., George D.L.;
RT "Stabilization of the MDM2 oncoprotein by interaction with the structurally
RT related MDMX protein.";
RL J. Biol. Chem. 274:38189-38196(1999).
RN [9]
RP FUNCTION IN TP53 ACTIVATION, PHOSPHORYLATION AT SER-342 AND SER-367 BY
RP CHEK2, UBIQUITINATION, AND INTERACTION WITH MDM2.
RX PubMed=16163388; DOI=10.1038/sj.emboj.7600812;
RA Chen L., Gilkes D.M., Pan Y., Lane W.S., Chen J.;
RT "ATM and Chk2-dependent phosphorylation of MDMX contribute to p53
RT activation after DNA damage.";
RL EMBO J. 24:3411-3422(2005).
RN [10]
RP FUNCTION IN TP53 ACTIVATION, PHOSPHORYLATION AT SER-367 BY CHEK1, AND
RP INTERACTION WITH YWHAG.
RX PubMed=16511572; DOI=10.1038/sj.emboj.7601010;
RA Jin Y., Dai M.S., Lu S.Z., Xu Y., Luo Z., Zhao Y., Lu H.;
RT "14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1,
RT resulting in p53 activation.";
RL EMBO J. 25:1207-1218(2006).
RN [11]
RP INTERACTION WITH USP2 AND MDM2, INDUCTION, UBIQUITINATION, AND
RP DEUBIQUITINATION BY USP2.
RX PubMed=19838211; DOI=10.1038/onc.2009.330;
RA Allende-Vega N., Sparks A., Lane D.P., Saville M.K.;
RT "MdmX is a substrate for the deubiquitinating enzyme USP2a.";
RL Oncogene 29:432-441(2010).
RN [12]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::aid-prot212>3.0.co;2-h;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line protein
RT expression map database.";
RL Proteomics 2:212-223(2002).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-342 AND SER-367, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [14]
RP STRUCTURE BY NMR OF 300-340.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the ZF-RANBP domain of p53-binding protein MDM4.";
RL Submitted (NOV-2005) to the PDB data bank.
RN [15]
RP INVOLVEMENT IN BMFS6, VARIANT BMFS6 MET-454, CHARACTERIZATION OF VARIANT
RP BMFS6 MET-454, FUNCTION, AND INTERACTION WITH MDM2.
RX PubMed=32300648; DOI=10.1126/sciadv.aay3511;
RA Toufektchan E., Lejour V., Durand R., Giri N., Draskovic I., Bardot B.,
RA Laplante P., Jaber S., Alter B.P., Londono-Vallejo J.A., Savage S.A.,
RA Toledo F.;
RT "Germline mutation of MDM4, a major p53 regulator, in a familial syndrome
RT of defective telomere maintenance.";
RL Sci. Adv. 6:eaay3511-eaay3511(2020).
CC -!- FUNCTION: Along with MDM2, contributes to TP53 regulation
CC (PubMed:32300648). Inhibits p53/TP53- and TP73/p73-mediated cell cycle
CC arrest and apoptosis by binding its transcriptional activation domain.
CC Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of
CC TP53 while maintaining suppression of TP53 transactivation and
CC apoptotic functions. {ECO:0000269|PubMed:16163388,
CC ECO:0000269|PubMed:16511572, ECO:0000269|PubMed:32300648}.
CC -!- SUBUNIT: Interacts with MDM2 (PubMed:16163388, PubMed:19838211,
CC PubMed:32300648). Interacts with TP53, TP73 and USP2. Found in a
CC trimeric complex with USP2, MDM2 and MDM4. Interacts (phosphorylated)
CC with YWHAG; negatively regulates MDM4 activity toward TP53.
CC {ECO:0000269|PubMed:16163388, ECO:0000269|PubMed:16511572,
CC ECO:0000269|PubMed:19838211, ECO:0000269|PubMed:32300648}.
CC -!- INTERACTION:
CC O15151; Q9NX04: AIRIM; NbExp=3; IntAct=EBI-398437, EBI-8643161;
CC O15151; P10415: BCL2; NbExp=4; IntAct=EBI-398437, EBI-77694;
CC O15151; Q7Z479: CAPN7; NbExp=3; IntAct=EBI-398437, EBI-10213454;
CC O15151; O95971: CD160; NbExp=6; IntAct=EBI-398437, EBI-4314390;
CC O15151; P48729: CSNK1A1; NbExp=2; IntAct=EBI-398437, EBI-1383726;
CC O15151; Q00987: MDM2; NbExp=10; IntAct=EBI-398437, EBI-389668;
CC O15151; Q13064: MKRN3; NbExp=9; IntAct=EBI-398437, EBI-2340269;
CC O15151; P41227: NAA10; NbExp=3; IntAct=EBI-398437, EBI-747693;
CC O15151; P06400: RB1; NbExp=4; IntAct=EBI-398437, EBI-491274;
CC O15151; Q9Y4L5: RNF115; NbExp=3; IntAct=EBI-398437, EBI-2129242;
CC O15151; P23297: S100A1; NbExp=2; IntAct=EBI-398437, EBI-743686;
CC O15151; P29034: S100A2; NbExp=2; IntAct=EBI-398437, EBI-752230;
CC O15151; P33763: S100A5; NbExp=2; IntAct=EBI-398437, EBI-7211732;
CC O15151; P04271: S100B; NbExp=3; IntAct=EBI-398437, EBI-458391;
CC O15151; P31947: SFN; NbExp=2; IntAct=EBI-398437, EBI-476295;
CC O15151; P04637: TP53; NbExp=19; IntAct=EBI-398437, EBI-366083;
CC O15151; P62837: UBE2D2; NbExp=2; IntAct=EBI-398437, EBI-347677;
CC O15151; Q93009: USP7; NbExp=15; IntAct=EBI-398437, EBI-302474;
CC O15151; O14972: VPS26C; NbExp=3; IntAct=EBI-398437, EBI-7207091;
CC O15151; P61964: WDR5; NbExp=3; IntAct=EBI-398437, EBI-540834;
CC O15151; P62258: YWHAE; NbExp=5; IntAct=EBI-398437, EBI-356498;
CC O15151; P61981: YWHAG; NbExp=7; IntAct=EBI-398437, EBI-359832;
CC O15151; P63104: YWHAZ; NbExp=2; IntAct=EBI-398437, EBI-347088;
CC O15151; Q9BRR0: ZKSCAN3; NbExp=3; IntAct=EBI-398437, EBI-1965777;
CC O15151; A0A0S2Z6X0: ZKSCAN4; NbExp=3; IntAct=EBI-398437, EBI-16431094;
CC O15151; Q3YBA8; NbExp=6; IntAct=EBI-398437, EBI-7852331;
CC O15151; P03255-2; Xeno; NbExp=3; IntAct=EBI-398437, EBI-6859460;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist.;
CC Name=1;
CC IsoId=O15151-1; Sequence=Displayed;
CC Name=2; Synonyms=MDMX-S;
CC IsoId=O15151-2; Sequence=VSP_035669;
CC Name=3; Synonyms=MDMX;
CC IsoId=O15151-3; Sequence=VSP_035670;
CC Name=HDMX211;
CC IsoId=O15151-4; Sequence=VSP_042563;
CC Name=5;
CC IsoId=O15151-5; Sequence=VSP_043145;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested with high levels in
CC thymus.
CC -!- INDUCTION: Down-regulated by cisplatin (at protein level).
CC {ECO:0000269|PubMed:19838211}.
CC -!- DOMAIN: Region I is sufficient for binding TP53 and inhibiting its G1
CC arrest and apoptosis functions. It also binds TP73. Region II contains
CC most of a central acidic region and a putative C4-type zinc finger. The
CC RING finger domain which coordinates two molecules of zinc mediates the
CC heterooligomerization with MDM2.
CC -!- PTM: Phosphorylated. Phosphorylation at Ser-367 promotes interaction
CC with YWHAG and subsequent ubiquitination and degradation.
CC Phosphorylation at Ser-342 also induces ubiquitination and degradation
CC but to a lower extent. {ECO:0000269|PubMed:16163388,
CC ECO:0000269|PubMed:16511572, ECO:0000269|PubMed:19838211}.
CC -!- PTM: Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on
CC the other hand stabilizes the MDM4 protein.
CC {ECO:0000269|PubMed:19838211}.
CC -!- MASS SPECTROMETRY: Mass=54863.3; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:11840567};
CC -!- DISEASE: Bone marrow failure syndrome 6 (BMFS6) [MIM:618849]: A form of
CC bone marrow failure syndrome, a heterogeneous group of life-threatening
CC disorders characterized by hematopoietic defects in association with a
CC range of variable extra-hematopoietic manifestations. BMFS6 is an
CC autosomal dominant form characterized by intermittent neutropenia,
CC lymphopenia, or anemia associated with hypocellular bone marrow, and
CC increased susceptibility to cancer. {ECO:0000269|PubMed:32300648}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: [Isoform HDMX211]: Cancer-specific isoform, may
CC counteract MDM2/MDM4-mediated p53 degradation. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/mdm4/";
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DR EMBL; AF007111; AAB62928.1; -; mRNA.
DR EMBL; AY923176; AAY22054.1; -; mRNA.
DR EMBL; AK223228; BAD96948.1; -; mRNA.
DR EMBL; AY207458; AAO13494.1; -; Genomic_DNA.
DR EMBL; AL512306; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC067299; AAH67299.1; -; mRNA.
DR EMBL; BC105106; AAI05107.1; -; mRNA.
DR CCDS; CCDS1447.1; -. [O15151-1]
DR CCDS; CCDS55674.1; -. [O15151-5]
DR CCDS; CCDS55675.1; -. [O15151-4]
DR RefSeq; NP_001191100.1; NM_001204171.1. [O15151-5]
DR RefSeq; NP_001191101.1; NM_001204172.1. [O15151-4]
DR RefSeq; NP_001265445.1; NM_001278516.1.
DR RefSeq; NP_001265446.1; NM_001278517.1.
DR RefSeq; NP_001265447.1; NM_001278518.1.
DR RefSeq; NP_001265448.1; NM_001278519.1.
DR RefSeq; NP_002384.2; NM_002393.4. [O15151-1]
DR PDB; 2CR8; NMR; -; A=300-339.
DR PDB; 2MWY; NMR; -; A=23-111.
DR PDB; 2N06; NMR; -; A=23-111.
DR PDB; 2N0U; NMR; -; A=23-111.
DR PDB; 2N0W; NMR; -; A=23-111.
DR PDB; 2N14; NMR; -; A=23-111.
DR PDB; 2VJE; X-ray; 2.20 A; B/D=428-490.
DR PDB; 2VJF; X-ray; 2.30 A; B/D=428-490.
DR PDB; 2VYR; X-ray; 2.00 A; A/B/C/D=16-116.
DR PDB; 3DAB; X-ray; 1.90 A; A/C/E/G=23-111.
DR PDB; 3EQY; X-ray; 1.63 A; A/B=24-108.
DR PDB; 3FDO; X-ray; 1.40 A; A=23-111.
DR PDB; 3FE7; X-ray; 1.35 A; A=14-111.
DR PDB; 3FEA; X-ray; 1.33 A; A=14-111.
DR PDB; 3JZO; X-ray; 1.80 A; A=23-111.
DR PDB; 3JZP; X-ray; 1.74 A; A=23-111.
DR PDB; 3JZQ; X-ray; 1.80 A; A/B=23-111.
DR PDB; 3LBJ; X-ray; 1.50 A; E=23-111.
DR PDB; 3MQR; X-ray; 1.80 A; B=395-404.
DR PDB; 3U15; X-ray; 1.80 A; A/B/C/D=14-111.
DR PDB; 4RXZ; X-ray; 1.55 A; A/B=24-108.
DR PDB; 5MNJ; X-ray; 2.16 A; D/H=427-490.
DR PDB; 5UML; X-ray; 3.00 A; A/B/E/G=24-108.
DR PDB; 5VK1; X-ray; 2.69 A; A/C/E/G/I/K/M/O=24-108.
DR PDB; 6Q9Q; X-ray; 2.10 A; A/B/C/D=14-111.
DR PDB; 6Q9S; X-ray; 2.40 A; A/B/C=14-111.
DR PDB; 6Q9U; X-ray; 2.40 A; A=14-111.
DR PDB; 6Q9W; X-ray; 1.55 A; A/B=14-111.
DR PDB; 6Q9Y; X-ray; 1.20 A; A/B=14-111.
DR PDB; 6YR5; X-ray; 2.25 A; O/P/Q/R=361-374.
DR PDB; 6YR7; X-ray; 2.10 A; C/Q=335-374.
DR PDB; 7C3Q; X-ray; 1.80 A; A=23-108.
DR PDB; 7C3Y; X-ray; 1.63 A; A=23-108.
DR PDB; 7C44; X-ray; 1.65 A; A=23-108.
DR PDB; 7EL4; X-ray; 2.11 A; A=23-111.
DR PDB; 7KJN; X-ray; 2.80 A; A=24-108.
DR PDB; 7MLA; NMR; -; A=428-490.
DR PDB; 8HDG; X-ray; 1.73 A; A/B/C/D=23-111.
DR PDB; 8IA5; X-ray; 1.93 A; A=23-111.
DR PDBsum; 2CR8; -.
DR PDBsum; 2MWY; -.
DR PDBsum; 2N06; -.
DR PDBsum; 2N0U; -.
DR PDBsum; 2N0W; -.
DR PDBsum; 2N14; -.
DR PDBsum; 2VJE; -.
DR PDBsum; 2VJF; -.
DR PDBsum; 2VYR; -.
DR PDBsum; 3DAB; -.
DR PDBsum; 3EQY; -.
DR PDBsum; 3FDO; -.
DR PDBsum; 3FE7; -.
DR PDBsum; 3FEA; -.
DR PDBsum; 3JZO; -.
DR PDBsum; 3JZP; -.
DR PDBsum; 3JZQ; -.
DR PDBsum; 3LBJ; -.
DR PDBsum; 3MQR; -.
DR PDBsum; 3U15; -.
DR PDBsum; 4RXZ; -.
DR PDBsum; 5MNJ; -.
DR PDBsum; 5UML; -.
DR PDBsum; 5VK1; -.
DR PDBsum; 6Q9Q; -.
DR PDBsum; 6Q9S; -.
DR PDBsum; 6Q9U; -.
DR PDBsum; 6Q9W; -.
DR PDBsum; 6Q9Y; -.
DR PDBsum; 6YR5; -.
DR PDBsum; 6YR7; -.
DR PDBsum; 7C3Q; -.
DR PDBsum; 7C3Y; -.
DR PDBsum; 7C44; -.
DR PDBsum; 7EL4; -.
DR PDBsum; 7KJN; -.
DR PDBsum; 7MLA; -.
DR PDBsum; 8HDG; -.
DR PDBsum; 8IA5; -.
DR AlphaFoldDB; O15151; -.
DR BMRB; O15151; -.
DR SMR; O15151; -.
DR BioGRID; 110359; 104.
DR ComplexPortal; CPX-6093; p53-MDM2-MDM4 transcriptional regulation complex.
DR ComplexPortal; CPX-663; p53-MDM4 transcriptional regulation complex.
DR CORUM; O15151; -.
DR DIP; DIP-24199N; -.
DR IntAct; O15151; 51.
DR MINT; O15151; -.
DR STRING; 9606.ENSP00000356150; -.
DR BindingDB; O15151; -.
DR ChEMBL; CHEMBL1255126; -.
DR MoonDB; O15151; Predicted.
DR iPTMnet; O15151; -.
DR PhosphoSitePlus; O15151; -.
DR BioMuta; MDM4; -.
DR EPD; O15151; -.
DR jPOST; O15151; -.
DR MassIVE; O15151; -.
DR MaxQB; O15151; -.
DR PaxDb; 9606-ENSP00000356150; -.
DR PeptideAtlas; O15151; -.
DR ProteomicsDB; 48474; -. [O15151-1]
DR ProteomicsDB; 48475; -. [O15151-2]
DR ProteomicsDB; 48477; -. [O15151-4]
DR ProteomicsDB; 48478; -. [O15151-5]
DR ABCD; O15151; 1 sequenced antibody.
DR Antibodypedia; 20673; 869 antibodies from 38 providers.
DR DNASU; 4194; -.
DR Ensembl; ENST00000367182.8; ENSP00000356150.3; ENSG00000198625.14. [O15151-1]
DR Ensembl; ENST00000367183.7; ENSP00000356151.3; ENSG00000198625.14. [O15151-4]
DR Ensembl; ENST00000454264.6; ENSP00000396840.2; ENSG00000198625.14. [O15151-5]
DR GeneID; 4194; -.
DR KEGG; hsa:4194; -.
DR MANE-Select; ENST00000367182.8; ENSP00000356150.3; NM_002393.5; NP_002384.2.
DR UCSC; uc001hay.3; human. [O15151-1]
DR AGR; HGNC:6974; -.
DR CTD; 4194; -.
DR DisGeNET; 4194; -.
DR GeneCards; MDM4; -.
DR HGNC; HGNC:6974; MDM4.
DR HPA; ENSG00000198625; Low tissue specificity.
DR MalaCards; MDM4; -.
DR MIM; 602704; gene.
DR MIM; 618849; phenotype.
DR neXtProt; NX_O15151; -.
DR OpenTargets; ENSG00000198625; -.
DR PharmGKB; PA30719; -.
DR VEuPathDB; HostDB:ENSG00000198625; -.
DR eggNOG; ENOG502QQNV; Eukaryota.
DR GeneTree; ENSGT00530000063539; -.
DR HOGENOM; CLU_1618400_0_0_1; -.
DR InParanoid; O15151; -.
DR OMA; IPDCRRT; -.
DR OrthoDB; 2916169at2759; -.
DR PhylomeDB; O15151; -.
DR TreeFam; TF105306; -.
DR PathwayCommons; O15151; -.
DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence.
DR Reactome; R-HSA-2559585; Oncogene Induced Senescence.
DR Reactome; R-HSA-5689880; Ub-specific processing proteases.
DR Reactome; R-HSA-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
DR Reactome; R-HSA-6804760; Regulation of TP53 Activity through Methylation.
DR Reactome; R-HSA-69541; Stabilization of p53.
DR SignaLink; O15151; -.
DR SIGNOR; O15151; -.
DR BioGRID-ORCS; 4194; 95 hits in 1224 CRISPR screens.
DR ChiTaRS; MDM4; human.
DR EvolutionaryTrace; O15151; -.
DR GeneWiki; MDM4; -.
DR GenomeRNAi; 4194; -.
DR Pharos; O15151; Tchem.
DR PRO; PR:O15151; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; O15151; Protein.
DR Bgee; ENSG00000198625; Expressed in nipple and 196 other cell types or tissues.
DR ExpressionAtlas; O15151; baseline and differential.
DR Genevisible; O15151; HS.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0017053; C:transcription repressor complex; IPI:ComplexPortal.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; IBA:GO_Central.
DR GO; GO:0008270; F:zinc ion binding; TAS:UniProtKB.
DR GO; GO:0003283; P:atrial septum development; ISS:BHF-UCL.
DR GO; GO:0003181; P:atrioventricular valve morphogenesis; ISS:BHF-UCL.
DR GO; GO:0071456; P:cellular response to hypoxia; IEP:UniProtKB.
DR GO; GO:0030330; P:DNA damage response, signal transduction by p53 class mediator; IEP:UniProtKB.
DR GO; GO:0003203; P:endocardial cushion morphogenesis; ISS:BHF-UCL.
DR GO; GO:0003170; P:heart valve development; ISS:BHF-UCL.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; TAS:ProtInc.
DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IDA:ComplexPortal.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IEP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0065003; P:protein-containing complex assembly; IDA:UniProtKB.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:InterPro.
DR GO; GO:0003281; P:ventricular septum development; ISS:BHF-UCL.
DR CDD; cd17673; MDM4; 1.
DR CDD; cd16784; mRING-HC-C2H2C4_MDM4; 1.
DR Gene3D; 1.10.245.10; SWIB/MDM2 domain; 1.
DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 1.
DR Gene3D; 2.30.30.380; Zn-finger domain of Sec23/24; 1.
DR IDEAL; IID00005; -.
DR InterPro; IPR015458; MDM4.
DR InterPro; IPR016495; p53_neg-reg_MDM_2/4.
DR InterPro; IPR036885; SWIB_MDM2_dom_sf.
DR InterPro; IPR003121; SWIB_MDM2_domain.
DR InterPro; IPR001876; Znf_RanBP2.
DR InterPro; IPR036443; Znf_RanBP2_sf.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR12183; MITOCHONDRIAL UBIQUITIN LIGASE ACTIVATOR OF NFKB 1; 1.
DR PANTHER; PTHR12183:SF37; PROTEIN MDM4; 1.
DR Pfam; PF13920; zf-C3HC4_3; 1.
DR Pfam; PF00641; zf-RanBP; 1.
DR PIRSF; PIRSF500699; MDM4; 1.
DR PIRSF; PIRSF006748; p53_MDM_2/4; 1.
DR SUPFAM; SSF90209; Ran binding protein zinc finger-like; 1.
DR SUPFAM; SSF47592; SWIB/MDM2 domain; 1.
DR PROSITE; PS51925; SWIB_MDM2; 1.
DR PROSITE; PS01358; ZF_RANBP2_1; 1.
DR PROSITE; PS50199; ZF_RANBP2_2; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Disease variant; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Ubl conjugation; Zinc;
KW Zinc-finger.
FT CHAIN 1..490
FT /note="Protein Mdm4"
FT /id="PRO_0000157336"
FT DOMAIN 25..108
FT /note="SWIB/MDM2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01273"
FT ZN_FING 300..329
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT ZN_FING 437..478
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 129..160
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 246..332
FT /note="Region II"
FT REGION 393..490
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000269|PubMed:19838211"
FT MOTIF 442..445
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 141..160
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 342
FT /note="Phosphoserine; by CHEK2"
FT /evidence="ECO:0000269|PubMed:16163388,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 367
FT /note="Phosphoserine; by CHEK1 and CHEK2"
FT /evidence="ECO:0000269|PubMed:16163388,
FT ECO:0000269|PubMed:16511572, ECO:0007744|PubMed:23186163"
FT VAR_SEQ 27..352
FT /note="Missing (in isoform HDMX211)"
FT /evidence="ECO:0000303|PubMed:16266988"
FT /id="VSP_042563"
FT VAR_SEQ 109..490
FT /note="LATATTDAAQTLALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPT
FT SEHKCIHSREDEDLIENLAQDETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTD
FT LQTNQDVGTAIVSDTTDDLWFLNESVSEQLGVGIKVEAADTEQTSEEVGKVSDKKVIEV
FT GKNDDLEDSKSLSDDTDVEVTSEDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKL
FT THSLSTSDITAIPEKENEGNDVPDCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLD
FT LAHSSESQETISSMGEQLDNLSEQRTDTENMEDCQNLLKPCSLCEKRPRDGNIIHGRTG
FT HLVTCFHCARRLKKAGASCPICKKEIQLVIKVFIA -> SASNNTARCNRILQSQKKN
FT (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_035669"
FT VAR_SEQ 109..490
FT /note="LATATTDAAQTLALAQDHSMDIPSQDQLKQSAEESSTSRKRTTEDDIPTLPT
FT SEHKCIHSREDEDLIENLAQDETSRLDLGFEEWDVAGLPWWFLGNLRSNYTPRSNGSTD
FT LQTNQDVGTAIVSDTTDDLWFLNESVSEQLGVGIKVEAADTEQTSEEVGKVSDKKVIEV
FT GKNDDLEDSKSLSDDTDVEVTSEDEWQCTECKKFNSPSKRYCFRCWALRKDWYSDCSKL
FT THSLSTSDITAIPEKENEGNDVPDCRRTISAPVVRPKDAYIKKENSKLFDPCNSVEFLD
FT LAHSSESQETISSMGEQLDNLSEQRTDTENMEDCQNLLKPCSLCEKRPRDGNIIHGRTG
FT HLVTCFHCARRLKKAGASCPICKKEIQLVIKVFIA -> SASNNTDAAQTLALAQDHT
FT (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_035670"
FT VAR_SEQ 225..274
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_043145"
FT VARIANT 175
FT /note="I -> T (in dbSNP:rs4252716)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_017106"
FT VARIANT 406
FT /note="T -> I (in dbSNP:rs4252741)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_017107"
FT VARIANT 454
FT /note="T -> M (in BMFS6; altered capacity to interact with
FT MDM2 RING domain in a yeast two-hybrid assay; no effect on
FT ATP binding; expressed at lower levels than wild-type; when
FT expressed in a mouse model, leads to increased TP53
FT activity, decreased telomerase length and ultimately to
FT bone marrow failure; dbSNP:rs1270135772)"
FT /evidence="ECO:0000269|PubMed:32300648"
FT /id="VAR_084553"
FT MUTAGEN 437
FT /note="C->G: Fails to interact with MDM2."
FT /evidence="ECO:0000269|PubMed:10608892"
FT CONFLICT 94
FT /note="D -> N (in Ref. 1; AAB62928)"
FT /evidence="ECO:0000305"
FT STRAND 27..29
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT HELIX 31..39
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT HELIX 49..62
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT STRAND 68..70
FT /evidence="ECO:0007829|PDB:4RXZ"
FT STRAND 73..75
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:7KJN"
FT HELIX 80..85
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT HELIX 96..105
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:6Q9Y"
FT STRAND 307..309
FT /evidence="ECO:0007829|PDB:2CR8"
FT TURN 321..323
FT /evidence="ECO:0007829|PDB:2CR8"
FT HELIX 343..345
FT /evidence="ECO:0007829|PDB:6YR7"
FT HELIX 429..434
FT /evidence="ECO:0007829|PDB:5MNJ"
FT TURN 438..440
FT /evidence="ECO:0007829|PDB:5MNJ"
FT STRAND 442..445
FT /evidence="ECO:0007829|PDB:5MNJ"
FT STRAND 447..451
FT /evidence="ECO:0007829|PDB:5MNJ"
FT STRAND 454..459
FT /evidence="ECO:0007829|PDB:5MNJ"
FT HELIX 461..469
FT /evidence="ECO:0007829|PDB:5MNJ"
FT TURN 475..477
FT /evidence="ECO:0007829|PDB:5MNJ"
FT STRAND 483..489
FT /evidence="ECO:0007829|PDB:5MNJ"
SQ SEQUENCE 490 AA; 54864 MW; 415E6FA5A0C69857 CRC64;
MTSFSTSAQC STSDSACRIS PGQINQVRPK LPLLKILHAA GAQGEMFTVK EVMHYLGQYI
MVKQLYDQQE QHMVYCGGDL LGELLGRQSF SVKDPSPLYD MLRKNLVTLA TATTDAAQTL
ALAQDHSMDI PSQDQLKQSA EESSTSRKRT TEDDIPTLPT SEHKCIHSRE DEDLIENLAQ
DETSRLDLGF EEWDVAGLPW WFLGNLRSNY TPRSNGSTDL QTNQDVGTAI VSDTTDDLWF
LNESVSEQLG VGIKVEAADT EQTSEEVGKV SDKKVIEVGK NDDLEDSKSL SDDTDVEVTS
EDEWQCTECK KFNSPSKRYC FRCWALRKDW YSDCSKLTHS LSTSDITAIP EKENEGNDVP
DCRRTISAPV VRPKDAYIKK ENSKLFDPCN SVEFLDLAHS SESQETISSM GEQLDNLSEQ
RTDTENMEDC QNLLKPCSLC EKRPRDGNII HGRTGHLVTC FHCARRLKKA GASCPICKKE
IQLVIKVFIA
//
