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Reviewed, UniProtKB/Swiss-Prot Q00987 (MDM2_HUMAN)

Last modified November 25, 2008. Version 120. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    E3 ubiquitin-protein ligase Mdm2
    EC=6.3.2.-
Alternative name(s):
    p53-binding protein Mdm2
    Oncoprotein Mdm2
    Double minute 2 protein
    Hdm2
Gene names
Name: MDM2
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length491 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

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General annotation (Comments)

Function

Inhibits TP53/p53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Functions as a ubiquitin ligase E3, in the presence of E1 and E2, toward p53 and itself. Permits the nuclear export of p53 and targets it for proteasome-mediated proteolysis.

Subunit structure

Binds p53, p73, ARF(P14), ribosomal protein L5 and specifically to RNA. Can interact also with retinoblastoma protein (RB), E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with TP53/p53 and WWOX. Interacts with CDKN2AIP, MTBP, TBRG1, USP7, PYHIN1 and UBXN6. Isoform Mdm2-F does not interact with TP53/p53. Interacts with and ubiquitinates HIV-1 Tat.

Subcellular location

Nucleus › nucleoplasm. Cytoplasm. Nucleus › nucleolus. 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.

Tissue specificity

Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.

Induction

By DNA damage.

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.

Post-translational modification

Phosphorylated in response to ionizing radiation in an ATM-dependent manner.

Auto-ubiquitinated; which leads to proteasomal degradation.

Involvement in disease

Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.

Miscellaneous

MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.

Sequence similarities

Belongs to the MDM2/MDM4 family.

Contains 1 RanBP2-type zinc finger.

Contains 1 RING-type zinc finger.

Contains 1 SWIB domain.

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Ontologies

Keywords

   Biological processHost-virus interaction
Ubl conjugation pathway
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityAlternative splicing
   DiseaseProto-oncogene
   DomainZinc-finger
   LigandMetal-binding
Zinc
   Molecular functionLigase
   PTMPhosphoprotein
Ubl conjugation
   Technical term3D-structure

Gene Ontology (GO)

   Biological processinterspecies interaction between organisms

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of cell proliferation

Traceable author statement. Source: ProtInc

negative regulation of transcription from RNA polymerase II promoter

Inferred from direct assay. Source: UniProtKB

protein complex assembly Ref.13

Inferred from direct assay. Source: UniProtKB

protein ubiquitination Ref.12

Inferred from direct assay. Source: UniProtKB

regulation of protein catabolic process

Inferred from direct assay. Source: UniProtKB

ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular componentcytosol

Inferred from Experiment. Source: Reactome

insoluble fraction

Inferred from direct assay. Source: UniProtKB

nucleolus Ref.16

Inferred from direct assay. Source: UniProtKB

nucleoplasm Ref.16

Inferred from direct assay. Source: UniProtKB

   Molecular functionenzyme binding

Inferred from physical interaction. Source: UniProtKB

identical protein binding

Inferred from physical interaction. Source: IntAct

negative regulator of basal transcription activity

Inferred from direct assay. Source: UniProtKB

ubiquitin-protein ligase activity Ref.12

Inferred from direct assay. Source: UniProtKB

zinc ion binding Ref.15

Inferred from direct assay. Source: UniProtKB

Complete GO annotation...

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Alternative products

This entry describes 10 isoforms produced by alternative splicing. [Align] [Select]
Isoform Mdm2 (identifier: Q00987-1)

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-A (identifier: Q00987-2)

The sequence of this isoform differs from the canonical sequence as follows:
     28-222: Missing.
Isoform Mdm2-A1 (identifier: Q00987-3)

The sequence of this isoform differs from the canonical sequence as follows:
     28-222: Missing.
     275-300: Missing.
Isoform Mdm2-B (identifier: Q00987-4)

The sequence of this isoform differs from the canonical sequence as follows:
     28-300: Missing.
Isoform Mdm2-C (identifier: Q00987-5)

The sequence of this isoform differs from the canonical sequence as follows:
     53-222: Missing.
Isoform Mdm2-D (identifier: Q00987-6)

The sequence of this isoform differs from the canonical sequence as follows:
     30-388: Missing.
Isoform Mdm2-E (identifier: Q00987-7)

The sequence of this isoform differs from the canonical sequence as follows:
     76-102: YCSNDLLGDLFGVPSFSVKEHRKIYTM → NDCANLFPLVDLSIRELYISNYITLGI
     103-491: Missing.
Isoform Mdm2-alpha (identifier: Q00987-8)

The sequence of this isoform differs from the canonical sequence as follows:
     1-61: Missing.
Isoform Mdm2-F (identifier: Q00987-9)

The sequence of this isoform differs from the canonical sequence as follows:
     53-97: Missing.
Isoform Mdm2-G (identifier: Q00987-10)

The sequence of this isoform differs from the canonical sequence as follows:
     115-169: Missing.

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 491491E3 ubiquitin-protein ligase Mdm2
PRO_0000157332

Regions

Domain27 – 10781SWIB
Zinc finger299 – 32830RanBP2-type
Zinc finger438 – 47942RING-type
Region150 – 23081Interaction with PYHIN1
Region170 – 306137Interaction with MTBP By similarity
Region210 – 30495ARF-binding
Region223 – 23210Interaction with USP7
Region242 – 33190Region II
Motif179 – 1857Nuclear localization signal Potential
Motif190 – 20213Nuclear export signal
Motif466 – 4738Nucleolar localization signal Potential
Compositional bias210 – 2156Poly-Ser
Compositional bias243 – 30159Asp/Glu-rich (acidic)

Natural variations

Alternative sequence1 – 6161Missing in isoform Mdm2-alpha.
VSP_003207
Alternative sequence28 – 300273Missing in isoform Mdm2-B.
VSP_003209
Alternative sequence28 – 222195Missing in isoform Mdm2-A and isoform Mdm2-A1.
VSP_003208
Alternative sequence30 – 388359Missing in isoform Mdm2-D.
VSP_003210
Alternative sequence53 – 222170Missing in isoform Mdm2-C.
VSP_003211
Alternative sequence53 – 9745Missing in isoform Mdm2-F.
VSP_022578
Alternative sequence76 – 10227YCSND…KIYTM → NDCANLFPLVDLSIRELYIS NYITLGI in isoform Mdm2-E.
VSP_003212
Alternative sequence103 – 491389Missing in isoform Mdm2-E.
VSP_003213
Alternative sequence115 – 16955Missing in isoform Mdm2-G.
VSP_022579
Alternative sequence275 – 30026Missing in isoform Mdm2-A1.
VSP_003214

Experimental info

Mutagenesis3051C → S: No loss of ubiquitin ligase E3 activity
Mutagenesis3741C → T: No loss of ubiquitin ligase E3 activity
Mutagenesis4381C → L: No loss of ubiquitin ligase E3 activity
Mutagenesis4411C → G: Fails to interact with MDM4
Mutagenesis4491C → A: Loss of ubiquitin ligase E3 activity
Mutagenesis4491C → S: No substantial decrease of ubiquitin ligase E3 activity
Mutagenesis4521H → A: Loss of ubiquitin ligase E3 activity
Mutagenesis4551T → A: Significant decrease of ubiquitin ligase E3 activity
Mutagenesis4571H → S: Loss of ubiquitin ligase E3 activity
Mutagenesis4611C → S: Loss of ubiquitin ligase E3 activity
Mutagenesis4641C → A: Loss of ubiquitin ligase E3 activity, enhances protein stability
Mutagenesis4751C → G: Loss of ubiquitin ligase E3 activity
Mutagenesis4781C → R: Fails to interact with MDM4
Mutagenesis4781C → S: Loss of ubiquitin ligase E3 activity
Sequence conflict171S → P in AAA82237. Ref.7

Secondary structure

1 ..................................... 491
Helix Strand Turn

Details...

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Sequences

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

Last modified April 1, 1993. Version 1.
Checksum: F37CE163876BC983

FASTA49155,233
        10         20         30         40         50         60 
MCNTNMSVPT DGAVTTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM KEVLFYLGQY 

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

       130        140        150        160        170        180 
SVSENRCHLE GGSDQKDLVQ ELQEEKPSSS HLVSRPSTSS RRRAISETEE NSDELSGERQ 

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

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

       310        320        330        340        350        360 
DYWKCTSCNE MNPPLPSHCN RCWALRENWL PEDKGKDKGE ISEKAKLENS TQAEEGFDVP 

       370        380        390        400        410        420 
DCKKTIVNDS RESCVEENDD KITQASQSQE SEDYSQPSTS SSIIYSSQED VKEFEREETQ 

       430        440        450        460        470        480 
DKEESVESSL PLNAIEPCVI CQGRPKNGCI VHGKTGHLMA CFTCAKKLKK RNKPCPVCRQ 

       490 
PIQMIVLTYF P

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Isoform Mdm2-A [UniParc].

Checksum: 9772439D74A4448B
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29633,140
Isoform Mdm2-A1 [UniParc].

Checksum: A3ED7CCFF670634E
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27030,265
Isoform Mdm2-B [UniParc].

Checksum: BB9C602F589EEC41
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21824,467