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P56950

- MDM2_CANFA

UniProt

P56950 - MDM2_CANFA

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Protein

E3 ubiquitin-protein ligase Mdm2

Gene

MDM2

Organism
Canis familiaris (Dog) (Canis lupus familiaris)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli

Functioni

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.By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri299 – 32830RanBP2-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri434 – 47542RING-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

  1. ligase activity Source: UniProtKB-KW
  2. zinc ion binding Source: InterPro

GO - Biological processi

  1. negative regulation of apoptotic process Source: InterPro
  2. negative regulation of cell cycle arrest Source: InterPro
  3. negative regulation of transcription from RNA polymerase II promoter Source: InterPro
  4. protein ubiquitination Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:MDM2
OrganismiCanis familiaris (Dog) (Canis lupus familiaris)
Taxonomic identifieri9615 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCarnivoraCaniformiaCanidaeCanis
ProteomesiUP000002254: Unplaced

Subcellular locationi

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 A in the nucleus By similarity.By similarity

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB-KW
  2. nucleolus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 487487E3 ubiquitin-protein ligase Mdm2PRO_0000157329Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei166 – 1661Phosphoserine; by SGK1By similarity
Modified residuei240 – 2401PhosphoserineBy similarity
Modified residuei242 – 2421PhosphoserineBy similarity
Modified residuei246 – 2461PhosphoserineBy similarity
Modified residuei260 – 2601PhosphoserineBy similarity
Modified residuei262 – 2621PhosphoserineBy similarity
Modified residuei382 – 3821Phosphoserine; by ATMBy similarity
Modified residuei391 – 3911Phosphoserine; by ATMBy similarity
Modified residuei403 – 4031Phosphoserine; by ATMBy similarity
Modified residuei415 – 4151Phosphothreonine; by ATMBy similarity
Modified residuei425 – 4251Phosphoserine; by ATMBy similarity

Post-translational modificationi

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.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.

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Expressioni

Tissue specificityi

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

Interactioni

Subunit structurei

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-F does 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 and RNF34; the interaction stabilizes MDM2. Interacts with MTA1 By similarity.By similarity

Structurei

3D structure databases

ProteinModelPortaliP56950.
SMRiP56950. Positions 1-118, 290-335, 428-487.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini27 – 10781SWIBAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni150 – 23081Interaction with PYHIN1 and necessary for interaction with RFFL and RNF34By similarityAdd
BLAST
Regioni170 – 306137Interaction with MTBPBy similarityAdd
BLAST
Regioni210 – 30495ARF-bindingAdd
BLAST
Regioni223 – 23210Interaction with USP7By similarity
Regioni242 – 33190Region IIAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi179 – 1857Nuclear localization signalSequence Analysis
Motifi190 – 20213Nuclear export signalAdd
BLAST
Motifi462 – 4698Nucleolar localization signalSequence Analysis

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi210 – 2156Poly-Ser
Compositional biasi243 – 30159Asp/Glu-rich (acidic)Add
BLAST

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 By similarity. Interacts with IGF1R By similarity.By similarity

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)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri299 – 32830RanBP2-typePROSITE-ProRule annotationAdd
BLAST
Zinc fingeri434 – 47542RING-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiNOG46328.
HOGENOMiHOG000293341.
HOVERGENiHBG013472.
InParanoidiP56950.
KOiK06643.

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]
PANTHERiPTHR10360:SF11. PTHR10360:SF11. 1 hit.
PfamiPF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view]
PIRSFiPIRSF500700. MDM2. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SMARTiSM00184. RING. 1 hit.
[Graphical view]
SUPFAMiSSF47592. SSF47592. 2 hits.
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. Align

Isoform Mdm2 (identifier: P56950-1) [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 GGAVSTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM
60 70 80 90 100
KEVIFYLGQY IMTKRLYDEK QQHIVYCSND LLGDLFGVPS FSVKEHRKIY
110 120 130 140 150
TMIYRNLVVV NQHEPSDSGT SVSENSCHRE GGSDQKDPVQ ELQEEKPSSS
160 170 180 190 200
DLISRPSTSS RRRTISETEE HADDLPGERQ RKRHKSDSIS LSFDESLALC
210 220 230 240 250
VIREICCERS SSSESTGTPS NPDLDAGVSE HSGDWLDQDS VSDQFSVEFE
260 270 280 290 300
VESLDSEDYS LSEEGQELSD EDDEVYRVTV YQAGESDTDS FEEDPEISLA
310 320 330 340 350
DYWKCTSCNE MNPPLPPHCN RCWALRENWL PEDKGKIPEK ATPENSTQVE
360 370 380 390 400
EGFDVPDCKK AAASDSRESC AEEIDDKITQ ASHSQESEDY SQPSTSNSII
410 420 430 440 450
YSSQEDVKEF EREETQDKEE IVESSFPLNA IEPCVICQGR PKNGCIVHGK
460 470 480
TGHLMACFTC AKKLKKRNKP CPVCRQPIQM IVLTYFP
Length:487
Mass (Da):54,696
Last modified:May 30, 2000 - v1
Checksum:i60CDB470A32A8E69
GO
Isoform Mdm2-alpha (identifier: P56950-2) [UniParc]FASTAAdd to Basket

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

Show »
Length:426
Mass (Da):48,034
Checksum:i43C0FFFB2004E4BF
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti11 – 111G → D in AAG42840. (PubMed:10597303)Curated
Sequence conflicti238 – 2392QD → HH in AAG42840. (PubMed:10597303)Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 6161Missing in isoform Mdm2-alpha. 1 PublicationVSP_003206Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF100705 mRNA. Translation: AAF67833.1.
AF322416 mRNA. Translation: AAG42840.1.
RefSeqiNP_001003103.1. NM_001003103.2.
UniGeneiCfa.702.

Genome annotation databases

GeneIDi403693.
KEGGicfa:403693.

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AF100705 mRNA. Translation: AAF67833.1 .
AF322416 mRNA. Translation: AAG42840.1 .
RefSeqi NP_001003103.1. NM_001003103.2.
UniGenei Cfa.702.

3D structure databases

ProteinModelPortali P56950.
SMRi P56950. Positions 1-118, 290-335, 428-487.
ModBasei Search...
MobiDBi Search...

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 403693.
KEGGi cfa:403693.

Organism-specific databases

CTDi 4193.

Phylogenomic databases

eggNOGi NOG46328.
HOGENOMi HOG000293341.
HOVERGENi HBG013472.
InParanoidi P56950.
KOi K06643.

Miscellaneous databases

NextBioi 20817197.

Family and domain databases

Gene3Di 1.10.245.10. 1 hit.
3.30.40.10. 1 hit.
InterProi IPR028340. 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 ]
PANTHERi PTHR10360:SF11. PTHR10360:SF11. 1 hit.
Pfami PF02201. SWIB. 1 hit.
PF00641. zf-RanBP. 1 hit.
[Graphical view ]
PIRSFi PIRSF500700. MDM2. 1 hit.
PIRSF006748. p53_MDM_2/4. 1 hit.
SMARTi SM00184. RING. 1 hit.
[Graphical view ]
SUPFAMi SSF47592. SSF47592. 2 hits.
PROSITEi PS01358. ZF_RANBP2_1. 1 hit.
PS50199. ZF_RANBP2_2. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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).

Entry informationi

Entry nameiMDM2_CANFA
AccessioniPrimary (citable) accession number: P56950
Secondary accession number(s): Q95KN5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: May 30, 2000
Last modified: October 29, 2014
This is version 118 of the entry and version 1 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. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3