MDM2_MESAU
ID MDM2_MESAU Reviewed; 466 AA.
AC Q60524;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 139.
DE RecName: Full=E3 ubiquitin-protein ligase Mdm2;
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:P23804};
DE AltName: Full=Double minute 2 protein;
DE AltName: Full=Oncoprotein Mdm2;
DE AltName: Full=RING-type E3 ubiquitin transferase Mdm2 {ECO:0000305};
DE AltName: Full=p53-binding protein Mdm2;
DE Flags: Fragment;
GN Name=MDM2;
OS Mesocricetus auratus (Golden hamster).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Mesocricetus.
OX NCBI_TaxID=10036;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Pancreas;
RX PubMed=7780969;
RA Chang K.W., Laconi S., Mangold K.A., Hubchak S., Scarpelli D.G.;
RT "Multiple genetic alterations in hamster pancreatic ductal
RT adenocarcinomas.";
RL Cancer Res. 55:2560-2568(1995).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of
CC p53/TP53, leading to its degradation by the proteasome. Inhibits
CC p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by
CC binding its transcriptional activation domain. Also acts as a ubiquitin
CC ligase E3 toward itself and ARRB1. Permits the nuclear export of
CC p53/TP53. Promotes proteasome-dependent ubiquitin-independent
CC degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated
CC apoptosis by inducing its ubiquitination and degradation. Component of
CC the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53.
CC Also a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links
CC growth factor and DNA damage response pathways. Mediates ubiquitination
CC and subsequent proteasome degradation of DYRK2 in nucleus.
CC Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal
CC degradation. Ubiquitinates DCX, leading to DCX degradation and
CC reduction of the dendritic spine density of olfactory bulb granule
CC cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4
CC which is required for AMPA receptor endocytosis (By similarity).
CC Negatively regulates NDUFS1, leading to decreased mitochondrial
CC respiration, marked oxidative stress, and commitment to the
CC mitochondrial pathway of apoptosis (By similarity). Binds NDUFS1
CC leading to its cytosolic retention rather than mitochondrial
CC localization resulting in decreased supercomplex assembly (interactions
CC between complex I and complex III), decreased complex I activity, ROS
CC production, and apoptosis (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:P23804};
CC -!- SUBUNIT: Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds
CC specifically to RNA. Can interact with RB1, E1A-associated protein
CC EP300 and the E2F1 transcription factor. Forms a ternary complex with
CC p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1 and
CC RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a
CC trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-
CC terminus and C-terminus). Interacts with MDM4. Part of a complex with
CC MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and
CC USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus)
CC with RASSF1 isoform A (via N-terminus); the interaction is independent
CC of TP53. Interacts with APEX1; leading to its ubiquitination and
CC degradation. Interacts with RYBP; this inhibits ubiquitination of TP53.
CC Identified in a complex with RYBP and p53/TP53. Also a component of the
CC TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53
CC stabilization and activity. Binds directly both p53/TP53 and TRIM28.
CC Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting
CC growth factor responses with DNA damage. Interacts directly with both
CC TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with
CC IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2
CC leading to its proteasomal degradation. Interacts with SNAI1; this
CC interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via
CC intracellular domain). Interacts with FHIT. Interacts with RFFL and
CC RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and
CC CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53.
CC Interacts with MTA1. Interacts with AARB2. Interacts with MTBP.
CC Interacts with PML. Interacts with RPL11. Interacts with TBRG1.
CC Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and
CC RPL11; the interaction is direct occurs in the nucleoplasm and
CC negatively regulates MDM2-mediated TP53 ubiquitination and degradation.
CC Interacts with ADGRB1; the interaction results in inhibition of MDM2-
CC mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4
CC stability and regulating synaptic plasticity. Interacts with RPL23A;
CC this interaction may promote p53/TP53 polyubiquitination (By
CC similarity). Interacts with NDUFS1 (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
CC -!- SUBCELLULAR LOCATION: Nucleus, nucleoplasm
CC {ECO:0000250|UniProtKB:P23804}. Cytoplasm
CC {ECO:0000250|UniProtKB:P23804}. Nucleus, nucleolus
CC {ECO:0000250|UniProtKB:P23804}. Nucleus {ECO:0000250|UniProtKB:Q00987}.
CC Note=Expressed predominantly in the nucleoplasm. Interaction with
CC ARF(P14) results in the localization of both proteins to the nucleolus.
CC The nucleolar localization signals in both ARF(P14) and MDM2 may be
CC necessary to allow efficient nucleolar localization of both proteins.
CC Colocalizes with RASSF1 isoform A in the nucleus (By similarity).
CC {ECO:0000250|UniProtKB:P23804, ECO:0000250|UniProtKB:Q00987}.
CC -!- DOMAIN: Region I is sufficient for binding p53 and inhibiting its G1
CC arrest and apoptosis functions. It also binds p73 and E2F1. Region II
CC contains most of a central acidic region required for interaction with
CC ribosomal protein L5 and a putative C4-type zinc finger. The RING
CC finger domain which coordinates two molecules of zinc interacts
CC specifically with RNA whether or not zinc is present and mediates the
CC heterooligomerization with MDM4. It is also essential for its ubiquitin
CC ligase E3 activity toward p53 and itself (By similarity).
CC {ECO:0000250}.
CC -!- PTM: Phosphorylation on Ser-156 by SGK1 activates ubiquitination of
CC p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM
CC upon DNA damage; this prevents oligomerization and E3 ligase
CC processivity and impedes constitutive p53/TP53 degradation (By
CC similarity). {ECO:0000250}.
CC -!- PTM: Autoubiquitination leads to proteasomal degradation; resulting in
CC p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by
CC TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases
CC deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7
CC leading to its stabilization. {ECO:0000250|UniProtKB:Q00987}.
CC -!- DISEASE: Note=The gene for this protein is overexpressed in some
CC tumors.
CC -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
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DR EMBL; U10982; AAC52425.1; -; mRNA.
DR AlphaFoldDB; Q60524; -.
DR SMR; Q60524; -.
DR STRING; 10036.XP_005066564.1; -.
DR eggNOG; ENOG502QQNV; Eukaryota.
DR Proteomes; UP000189706; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005730; C:nucleolus; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0008097; F:5S rRNA binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:InterPro.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0043021; F:ribonucleoprotein complex binding; ISS:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; ISS:UniProtKB.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; ISS:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0065008; P:regulation of biological quality; IEA:UniProt.
DR GO; GO:0051726; P:regulation of cell cycle; IEA:InterPro.
DR CDD; cd16783; mRING-HC-C2H2C4_MDM2; 1.
DR Gene3D; 1.10.245.10; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR028340; Mdm2.
DR InterPro; IPR015459; MDM2_E3_ligase.
DR InterPro; IPR044080; MDM2_mRING-HC-C2H2C4.
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; PTHR13844:SF15; PTHR13844:SF15; 1.
DR Pfam; PF02201; SWIB; 1.
DR Pfam; PF00641; zf-RanBP; 1.
DR PIRSF; PIRSF500700; MDM2; 1.
DR PIRSF; PIRSF006748; p53_MDM_2/4; 1.
DR SUPFAM; SSF47592; SSF47592; 2.
DR SUPFAM; SSF90209; SSF90209; 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 2: Evidence at transcript level;
KW Apoptosis; Cytoplasm; Metal-binding; Nucleus; Phosphoprotein;
KW Proto-oncogene; Reference proteome; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN <1..>466
FT /note="E3 ubiquitin-protein ligase Mdm2"
FT /id="PRO_0000157333"
FT DOMAIN 18..100
FT /note="SWIB/MDM2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01273"
FT ZN_FING 285..314
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT ZN_FING 419..460
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION <1..101
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION <1..92
FT /note="Sufficient to promote the mitochondrial pathway of
FT apoptosis"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 109..174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 140..216
FT /note="Interaction with PYHIN1 and necessary for
FT interaction with RFFL and RNF34"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 160..292
FT /note="Interaction with MTBP"
FT /evidence="ECO:0000250"
FT REGION 196..290
FT /note="ARF-binding"
FT REGION 197..223
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 209..218
FT /note="Interaction with USP7"
FT /evidence="ECO:0000250"
FT REGION 228..317
FT /note="Region II"
FT REGION 238..260
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 262..>466
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION 319..407
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 169..175
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 176..188
FT /note="Nuclear export signal"
FT MOTIF 447..454
FT /note="Nucleolar localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 152..174
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 197..212
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 319..368
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 369..389
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 390..406
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 156
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 176
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P23804"
FT MOD_RES 226
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 228
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 232
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 246
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 248
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 367
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 376
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 388
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 400
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT NON_TER 1
FT NON_TER 466
SQ SEQUENCE 466 AA; 52390 MW; 78A3042163C5F939 CRC64;
STDGAEGTSQ IPASEQETLV RPKPLFLKLL KSVGAQKDTY TMKEIILSWQ YIMTKRLYDE
KQQHIVYCSN DLLGDLFGVP SFSVKDHRKI HIMIYRNLVV VSQQETLQSG TSVSESRCQP
EGGSEQKDPV QEPQEEKSSS DSVSRPSTSS RRRTISETEE NADELPGDRQ RKRHRSLSFD
ESLALCVLRE ICCERSSSSE STDTPSNQDL DDGVSEHSGD WLDQDSVSDQ FSVEFEVESL
DSEDYSLSEG GQELSDEDDE VYRVTVYQSG ESDVDSFEGD PEISLADYWK CTSCNEMNPP
LPPLCNRCWT LRENWLPEDK EKDRGDASEE AKLEAEGLDV PDGKKATSSD SKESCTEEND
DKEIYTSQSQ ESEDYSQPST SSSIVYSSQE DVKEWEKEET ADKEENVESG FSLNAIEPCV
ICQGRPKNGC IVHGKTGHLM SCFPCAKKLK KRNKPCPVCR QPIQMI
