Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

E3 ubiquitin-protein ligase Mdm2

Gene

Mdm2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome (PubMed:15195100). Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain (By similarity). Also acts as a ubiquitin ligase E3 toward itself, ARRB1 and ARBB2 (PubMed:11588219). Permits the nuclear export of p53/TP53 (By similarity). Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein (By similarity). Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation (By similarity). Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53 (By similarity). Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways (By similarity). Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus (By similarity). Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (By similarity). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (PubMed:25088421).By similarity3 Publications

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri297 – 326RanBP2-typePROSITE-ProRule annotationAdd BLAST30
Zinc fingeri436 – 477RING-typePROSITE-ProRule annotationAdd BLAST42

GO - Molecular functioni

  • enzyme binding Source: MGI
  • ligase activity Source: MGI
  • p53 binding Source: BHF-UCL
  • scaffold protein binding Source: BHF-UCL
  • SUMO transferase activity Source: MGI
  • ubiquitin protein ligase activity Source: MGI
  • ubiquitin protein ligase binding Source: MGI
  • ubiquitin-protein transferase activity Source: MGI
  • zinc ion binding Source: MGI

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BRENDAi6.3.2.19. 3474.
ReactomeiR-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-2559585. Oncogene Induced Senescence.
R-MMU-399719. Trafficking of AMPA receptors.
R-MMU-5689880. Ub-specific processing proteases.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.
R-MMU-6804757. Regulation of TP53 Degradation.
R-MMU-6804760. Regulation of TP53 Activity through Methylation.
R-MMU-69541. Stabilization of p53.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase Mdm2 (EC:6.3.2.-)
Alternative name(s):
Double minute 2 protein
Oncoprotein Mdm2
p53-binding protein Mdm2
Gene namesi
Name:Mdm2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:96952. Mdm2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytosol Source: Ensembl
  • nuclear body Source: Ensembl
  • nucleolus Source: UniProtKB
  • nucleoplasm Source: MGI
  • nucleus Source: MGI
  • plasma membrane Source: Ensembl
  • protein complex Source: MGI
  • synapse Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Involvement in diseasei

The gene for this protein is amplified in a mouse tumor cell line.

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL3600279.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000186501 – 489E3 ubiquitin-protein ligase Mdm2Add BLAST489

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei163Phosphoserine; by SGK1By similarity1
Modified residuei183PhosphoserineCombined sources1
Modified residuei238PhosphoserineBy similarity1
Modified residuei240PhosphoserineBy similarity1
Modified residuei244PhosphoserineBy similarity1
Modified residuei258PhosphoserineBy similarity1
Modified residuei260PhosphoserineBy similarity1
Modified residuei394Phosphoserine; by ATMBy similarity1
Modified residuei406Phosphoserine; by ATMBy similarity1
Modified residuei417Phosphothreonine; by ATMBy similarity1
Modified residuei423Phosphoserine; by ATMBy similarity1
Modified residuei427Phosphoserine; by ATMBy similarity1

Post-translational modificationi

Phosphorylation on Ser-163 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation (By similarity).By similarity
Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization (By similarity).By similarity

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP23804.
PeptideAtlasiP23804.
PRIDEiP23804.

PTM databases

iPTMnetiP23804.
PhosphoSitePlusiP23804.

Miscellaneous databases

PMAP-CutDBQ91XK7.

Expressioni

Tissue specificityi

Ubiquitously expressed at low-level throughout embryo development and in adult tissues. MDM2-p90 is much more abundant than MDM2-p76 in testis, brain, heart, and kidney, but in the thymus, spleen, and intestine, the levels of the MDM2 proteins are roughly equivalent.1 Publication

Inductioni

By UV light (PubMed:10075719). Down-regulated by NPAS4 (PubMed:25088421).2 Publications

Gene expression databases

BgeeiENSMUSG00000020184.
CleanExiMM_MDM2.
ExpressionAtlasiP23804. baseline and differential.
GenevisibleiP23804. MM.

Interactioni

Subunit structurei

Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, UBXN6, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53. Interacts with MTA1 (By similarity). Interacts with AARB2 (PubMed:11588219). Interacts with MTBP (PubMed:10906133). Interacts with PML (PubMed:15195100). Interacts with RPL11 (PubMed:15195100). Interacts with TBRG1 (PubMed:17110379).By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Arrb1Q8BWG84EBI-641788,EBI-641778
Dlg4Q621083EBI-641788,EBI-300895
Hipk1O889043EBI-641788,EBI-692945
Mdm4O356182EBI-3386480,EBI-2603376
PLK1P533502EBI-641788,EBI-476768From a different organism.
Rassf5Q5EBH13EBI-641788,EBI-960530
Rpl11Q9CXW44EBI-641788,EBI-1548890
Rpl23P628302EBI-641788,EBI-2365752
Rpl5P479623EBI-641788,EBI-773940
Rps6kb1Q8BSK82EBI-641788,EBI-646423
Tp53P023405EBI-641788,EBI-474016

GO - Molecular functioni

  • enzyme binding Source: MGI
  • p53 binding Source: BHF-UCL
  • scaffold protein binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: MGI

Protein-protein interaction databases

BioGridi201372. 85 interactors.
DIPiDIP-24174N.
DIP-24196N.
IntActiP23804. 19 interactors.
MINTiMINT-139756.
STRINGi10090.ENSMUSP00000020408.

Structurei

3D structure databases

ProteinModelPortaliP23804.
SMRiP23804.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini27 – 107SWIBAdd BLAST81

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 110Necessary for interaction with USP2By similarityAdd BLAST110
Regioni147 – 228Interaction with PYHIN1 and necessary for interaction with RFFL and RNF34By similarityAdd BLAST82
Regioni167 – 304Interaction with MTBP1 PublicationAdd BLAST138
Regioni208 – 302ARF-bindingAdd BLAST95
Regioni221 – 230Interaction with USP7By similarity10
Regioni240 – 329Region IIAdd BLAST90
Regioni274 – 489Necessary for interaction with USP2By similarityAdd BLAST216

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi176 – 182Nuclear localization signalSequence analysis7
Motifi183 – 195Nuclear export signalAdd BLAST13
Motifi464 – 471Nucleolar localization signalSequence analysis8

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi203 – 213Poly-SerAdd BLAST11
Compositional biasi221 – 299Asp/Glu-rich (acidic)Add BLAST79

Domaini

Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.

Sequence similaritiesi

Belongs to the MDM2/MDM4 family.Curated
Contains 1 RanBP2-type zinc finger.PROSITE-ProRule annotation
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation
Contains 1 SWIB domain.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri297 – 326RanBP2-typePROSITE-ProRule annotationAdd BLAST30
Zinc fingeri436 – 477RING-typePROSITE-ProRule annotationAdd BLAST42

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IGXG. Eukaryota.
ENOG41125MP. LUCA.
GeneTreeiENSGT00530000063539.
HOGENOMiHOG000293341.
HOVERGENiHBG013472.
InParanoidiP23804.
KOiK06643.
OMAiGELPCKL.
OrthoDBiEOG091G0FYK.
TreeFamiTF105306.

Family and domain databases

Gene3Di1.10.245.10. 1 hit.
3.30.40.10. 1 hit.
InterProiIPR028340. Mdm2.
IPR015459. MDM2_E3_ligase.
IPR016495. p53_neg-reg_MDM_2/4.
IPR003121. SWIB_MDM2_domain.
IPR001876. Znf_RanBP2.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
PANTHERiPTHR13844:SF15. PTHR13844:SF15. 1 hit.
PfamiPF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view]
PIRSFiPIRSF500700. MDM2. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SUPFAMiSSF47592. SSF47592. 2 hits.
SSF90209. SSF90209. 1 hit.
PROSITEiPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing and alternative initiation. AlignAdd to basket

Isoform Mdm2-p90 (identifier: P23804-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MCNTNMSVST EGAASTSQIP ASEQETLVRP KPLLLKLLKS VGAQNDTYTM
60 70 80 90 100
KEIIFYIGQY IMTKRLYDEK QQHIVYCSND LLGDVFGVPS FSVKEHRKIY
110 120 130 140 150
AMIYRNLVAV SQQDSGTSLS ESRRQPEGGS DLKDPLQAPP EEKPSSSDLI
160 170 180 190 200
SRLSTSSRRR SISETEENTD ELPGERHRKR RRSLSFDPSL GLCELREMCS
210 220 230 240 250
GGSSSSSSSS SESTETPSHQ DLDDGVSEHS GDCLDQDSVS DQFSVEFEVE
260 270 280 290 300
SLDSEDYSLS DEGHELSDED DEVYRVTVYQ TGESDTDSFE GDPEISLADY
310 320 330 340 350
WKCTSCNEMN PPLPSHCKRC WTLRENWLPD DKGKDKVEIS EKAKLENSAQ
360 370 380 390 400
AEEGLDVPDG KKLTENDAKE PCAEEDSEEK AEQTPLSQES DDYSQPSTSS
410 420 430 440 450
SIVYSSQESV KELKEETQDK DESVESSFSL NAIEPCVICQ GRPKNGCIVH
460 470 480
GKTGHLMSCF TCAKKLKKRN KPCPVCRQPI QMIVLTYFN
Length:489
Mass (Da):54,558
Last modified:July 27, 2011 - v3
Checksum:i4ABF489A82038DF4
GO
Isoform Mdm2-p76 (identifier: P23804-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-49: Missing.

Note: Does not bind to p53. Can be produced by alternative initiation at Met-50 of isoform Mdm2-p90, but is produced more efficiently by alternative splicing.
Show »
Length:440
Mass (Da):49,351
Checksum:iC574909560CC1A5F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti203S → T in CAA41684 (PubMed:2026149).Curated1
Sequence conflicti419D → H in CAA41684 (PubMed:2026149).Curated1
Sequence conflicti486T → S in CAA41684 (PubMed:2026149).Curated1
Sequence conflicti486T → S in AAA91167 (PubMed:8917101).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0032151 – 49Missing in isoform Mdm2-p76. CuratedAdd BLAST49

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X58876 mRNA. Translation: CAA41684.1.
U40145 Genomic DNA. Translation: AAA91167.1.
U47944
, U47935, U47936, U47937, U47938, U47939, U47940, U47941, U47942, U47943 Genomic DNA. Translation: AAB09030.1.
U47934 mRNA. Translation: AAB09031.1.
AK004719 mRNA. Translation: BAB23502.1.
AK088638 mRNA. Translation: BAC40470.1.
BC050902 mRNA. Translation: AAH50902.1.
CCDSiCCDS24194.1. [P23804-1]
CCDS70110.1. [P23804-2]
PIRiS15349.
RefSeqiNP_001275515.1. NM_001288586.2. [P23804-2]
NP_034916.1. NM_010786.4. [P23804-1]
UniGeneiMm.22670.
Mm.447669.

Genome annotation databases

EnsembliENSMUST00000020408; ENSMUSP00000020408; ENSMUSG00000020184. [P23804-1]
ENSMUST00000105263; ENSMUSP00000100898; ENSMUSG00000020184. [P23804-2]
GeneIDi17246.
KEGGimmu:17246.
UCSCiuc007hdl.2. mouse. [P23804-1]

Keywords - Coding sequence diversityi

Alternative initiation, Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X58876 mRNA. Translation: CAA41684.1.
U40145 Genomic DNA. Translation: AAA91167.1.
U47944
, U47935, U47936, U47937, U47938, U47939, U47940, U47941, U47942, U47943 Genomic DNA. Translation: AAB09030.1.
U47934 mRNA. Translation: AAB09031.1.
AK004719 mRNA. Translation: BAB23502.1.
AK088638 mRNA. Translation: BAC40470.1.
BC050902 mRNA. Translation: AAH50902.1.
CCDSiCCDS24194.1. [P23804-1]
CCDS70110.1. [P23804-2]
PIRiS15349.
RefSeqiNP_001275515.1. NM_001288586.2. [P23804-2]
NP_034916.1. NM_010786.4. [P23804-1]
UniGeneiMm.22670.
Mm.447669.

3D structure databases

ProteinModelPortaliP23804.
SMRiP23804.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi201372. 85 interactors.
DIPiDIP-24174N.
DIP-24196N.
IntActiP23804. 19 interactors.
MINTiMINT-139756.
STRINGi10090.ENSMUSP00000020408.

Chemistry databases

ChEMBLiCHEMBL3600279.

PTM databases

iPTMnetiP23804.
PhosphoSitePlusiP23804.

Proteomic databases

PaxDbiP23804.
PeptideAtlasiP23804.
PRIDEiP23804.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000020408; ENSMUSP00000020408; ENSMUSG00000020184. [P23804-1]
ENSMUST00000105263; ENSMUSP00000100898; ENSMUSG00000020184. [P23804-2]
GeneIDi17246.
KEGGimmu:17246.
UCSCiuc007hdl.2. mouse. [P23804-1]

Organism-specific databases

CTDi4193.
MGIiMGI:96952. Mdm2.

Phylogenomic databases

eggNOGiENOG410IGXG. Eukaryota.
ENOG41125MP. LUCA.
GeneTreeiENSGT00530000063539.
HOGENOMiHOG000293341.
HOVERGENiHBG013472.
InParanoidiP23804.
KOiK06643.
OMAiGELPCKL.
OrthoDBiEOG091G0FYK.
TreeFamiTF105306.

Enzyme and pathway databases

BRENDAi6.3.2.19. 3474.
ReactomeiR-MMU-198323. AKT phosphorylates targets in the cytosol.
R-MMU-2559580. Oxidative Stress Induced Senescence.
R-MMU-2559585. Oncogene Induced Senescence.
R-MMU-399719. Trafficking of AMPA receptors.
R-MMU-5689880. Ub-specific processing proteases.
R-MMU-6804756. Regulation of TP53 Activity through Phosphorylation.
R-MMU-6804757. Regulation of TP53 Degradation.
R-MMU-6804760. Regulation of TP53 Activity through Methylation.
R-MMU-69541. Stabilization of p53.

Miscellaneous databases

ChiTaRSiMdm2. mouse.
PMAP-CutDBQ91XK7.
PROiP23804.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000020184.
CleanExiMM_MDM2.
ExpressionAtlasiP23804. baseline and differential.
GenevisibleiP23804. MM.

Family and domain databases

Gene3Di1.10.245.10. 1 hit.
3.30.40.10. 1 hit.
InterProiIPR028340. Mdm2.
IPR015459. MDM2_E3_ligase.
IPR016495. p53_neg-reg_MDM_2/4.
IPR003121. SWIB_MDM2_domain.
IPR001876. Znf_RanBP2.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
PANTHERiPTHR13844:SF15. PTHR13844:SF15. 1 hit.
PfamiPF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view]
PIRSFiPIRSF500700. MDM2. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SUPFAMiSSF47592. SSF47592. 2 hits.
SSF90209. SSF90209. 1 hit.
PROSITEiPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMDM2_MOUSE
AccessioniPrimary (citable) accession number: P23804
Secondary accession number(s): Q61040, Q64330, Q91XK7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1991
Last sequence update: July 27, 2011
Last modified: November 30, 2016
This is version 176 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.