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P56950 (MDM2_CANFA) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 113. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase Mdm2

EC=6.3.2.-
Alternative name(s):
Double minute 2 protein
Short name=Cdm2
p53-binding protein Mdm2
Gene names
Name:MDM2
OrganismCanis familiaris (Dog) (Canis lupus familiaris) [Reference proteome]
Taxonomic identifier9615 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis

Protein attributes

Sequence length487 AA.
Sequence statusComplete.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

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

Subunit structure

Binds p53/TP53, TP73/p73, ARF/P14, PML, RBL5 and RP11 and specifically to RNA. Can interact also with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, MTBP, RFWD3, TBRG1, USP7, PYHIN1, UBXN6, and RBBP6. Isoform Mdm2-Fdoes not interact with p53/TP53. Interacts with ARRB1 and ARRB2. Interacts (isoform 2)with PSMA3. Found in a trimeric complex with MDM2, MDM4 and UPB2. 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; the interaction leads 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 By similarity.

Subcellular location

Nucleusnucleoplasm By similarity. Cytoplasm By similarity. Nucleusnucleolus By similarity. Note: Expressed predominantly in the nucleoplasm. Interaction with ARF(P14) results in the localization of both proteins to the nucleolus. The nucleolar localization signals in both ARF(P14) and MDM2 may be necessary to allow efficient nucleolar localization of both proteins. Colocalizes with RASSF1 isoform Ain the nucleus By similarity.

Tissue specificity

Isoform Mdm2-alpha is present in lymphoid and testicular tissues.

Domain

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 By similarity. Interacts with IGF1R By similarity.

Post-translational modification

Phosphorylation on Ser-166 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.

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.

Sequence similarities

Belongs to the MDM2/MDM4 family.

Contains 1 RanBP2-type zinc finger.

Contains 1 RING-type zinc finger.

Contains 1 SWIB domain.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform Mdm2 (identifier: P56950-1)

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.
Isoform Mdm2-alpha (identifier: P56950-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-61: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 487487E3 ubiquitin-protein ligase Mdm2
PRO_0000157329

Regions

Domain27 – 10781SWIB
Zinc finger299 – 32830RanBP2-type
Zinc finger434 – 47542RING-type
Region150 – 23081Interaction with PYHIN1 and necessary for interaction with RFFL By similarity
Region170 – 306137Interaction with MTBP By similarity
Region210 – 30495ARF-binding
Region223 – 23210Interaction with USP7 By similarity
Region242 – 33190Region II
Motif179 – 1857Nuclear localization signal Potential
Motif190 – 20213Nuclear export signal
Motif462 – 4698Nucleolar localization signal Potential
Compositional bias210 – 2156Poly-Ser
Compositional bias243 – 30159Asp/Glu-rich (acidic)

Amino acid modifications

Modified residue1661Phosphoserine; by SGK1 By similarity
Modified residue2401Phosphoserine By similarity
Modified residue2421Phosphoserine By similarity
Modified residue2461Phosphoserine By similarity
Modified residue2601Phosphoserine By similarity
Modified residue2621Phosphoserine By similarity
Modified residue3821Phosphoserine; by ATM By similarity
Modified residue3911Phosphoserine; by ATM By similarity
Modified residue4031Phosphoserine; by ATM By similarity
Modified residue4151Phosphothreonine; by ATM By similarity
Modified residue4251Phosphoserine; by ATM By similarity

Natural variations

Alternative sequence1 – 6161Missing in isoform Mdm2-alpha.
VSP_003206

Experimental info

Sequence conflict111G → D in AAG42840. Ref.2
Sequence conflict238 – 2392QD → HH in AAG42840. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Isoform Mdm2 [UniParc].

Last modified May 30, 2000. Version 1.
Checksum: 60CDB470A32A8E69

FASTA48754,696
        10         20         30         40         50         60 
MCNTNMSVST GGAVSTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM KEVIFYLGQY 

        70         80         90        100        110        120 
IMTKRLYDEK QQHIVYCSND LLGDLFGVPS FSVKEHRKIY TMIYRNLVVV NQHEPSDSGT 

       130        140        150        160        170        180 
SVSENSCHRE GGSDQKDPVQ ELQEEKPSSS DLISRPSTSS RRRTISETEE HADDLPGERQ 

       190        200        210        220        230        240 
RKRHKSDSIS LSFDESLALC VIREICCERS SSSESTGTPS NPDLDAGVSE HSGDWLDQDS 

       250        260        270        280        290        300 
VSDQFSVEFE VESLDSEDYS LSEEGQELSD EDDEVYRVTV YQAGESDTDS FEEDPEISLA 

       310        320        330        340        350        360 
DYWKCTSCNE MNPPLPPHCN RCWALRENWL PEDKGKIPEK ATPENSTQVE EGFDVPDCKK 

       370        380        390        400        410        420 
AAASDSRESC AEEIDDKITQ ASHSQESEDY SQPSTSNSII YSSQEDVKEF EREETQDKEE 

       430        440        450        460        470        480 
IVESSFPLNA IEPCVICQGR PKNGCIVHGK TGHLMACFTC AKKLKKRNKP CPVCRQPIQM 


IVLTYFP 

« Hide

Isoform Mdm2-alpha [UniParc].

Checksum: 43C0FFFB2004E4BF
Show »

FASTA42648,034

References

[1]"Cloning, sequence analysis and expression of the cDNAs encoding the canine and equine homologues of the mouse double minute 2 (mdm2) proto-oncogene."
Nasir L., Burr P.D., McFarlane S.T., Gault E., Thompson H., Argyle D.J.
Cancer Lett. 152:9-13(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-484.
[2]"A novel exon within the mdm2 gene modulates translation initiation in vitro and disrupts the p53-binding domain of mdm2 protein."
Veldhoen N., Metcalfe S., Milner J.
Oncogene 18:7026-7033(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS MDM2 AND MDM2-ALPHA).

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF100705 mRNA. Translation: AAF67833.1.
AF322416 mRNA. Translation: AAG42840.1.
RefSeqNP_001003103.1. NM_001003103.2.
UniGeneCfa.702.

3D structure databases

ProteinModelPortalP56950.
SMRP56950. Positions 1-118, 290-335, 428-487.
ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID403693.
KEGGcfa:403693.

Organism-specific databases

CTD4193.

Phylogenomic databases

eggNOGNOG46328.
HOGENOMHOG000293341.
HOVERGENHBG013472.
InParanoidP56950.
KOK06643.

Family and domain databases

Gene3D1.10.245.10. 1 hit.
3.30.40.10. 1 hit.
InterProIPR028340. 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]
PANTHERPTHR10360:SF9. PTHR10360:SF9. 1 hit.
PfamPF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view]
PIRSFPIRSF500700. MDM2. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SMARTSM00184. RING. 1 hit.
[Graphical view]
SUPFAMSSF47592. SSF47592. 2 hits.
PROSITEPS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio20817197.

Entry information

Entry nameMDM2_CANFA
AccessionPrimary (citable) accession number: P56950
Secondary accession number(s): Q95KN5
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: May 30, 2000
Last modified: April 16, 2014
This is version 113 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families