MDM2_HORSE
ID MDM2_HORSE Reviewed; 491 AA.
AC P56951;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 30-MAY-2000, 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 Short=Edm2;
DE AltName: Full=RING-type E3 ubiquitin transferase Mdm2 {ECO:0000305};
DE AltName: Full=p53-binding protein Mdm2;
GN Name=MDM2;
OS Equus caballus (Horse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.
OX NCBI_TaxID=9796;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10754200; DOI=10.1016/s0304-3835(99)00427-9;
RA Nasir L., Burr P.D., McFarlane S.T., Gault E., Thompson H., Argyle D.J.;
RT "Cloning, sequence analysis and expression of the cDNAs encoding the canine
RT and equine homologues of the mouse double minute 2 (mdm2) proto-oncogene.";
RL Cancer Lett. 152:9-13(2000).
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-166 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 -!- SIMILARITY: Belongs to the MDM2/MDM4 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF121140; AAF28866.1; -; mRNA.
DR AlphaFoldDB; P56951; -.
DR BMRB; P56951; -.
DR SMR; P56951; -.
DR InParanoid; P56951; -.
DR Proteomes; UP000002281; 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:0002039; F:p53 binding; IBA:GO_Central.
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; IBA:GO_Central.
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 GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
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 Reference proteome; Transferase; Ubl conjugation; Ubl conjugation pathway;
KW Zinc; Zinc-finger.
FT CHAIN 1..491
FT /note="E3 ubiquitin-protein ligase Mdm2"
FT /id="PRO_0000157331"
FT DOMAIN 26..109
FT /note="SWIB/MDM2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01273"
FT ZN_FING 299..328
FT /note="RanBP2-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00322"
FT ZN_FING 438..479
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..110
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION 1..101
FT /note="Sufficient to promote the mitochondrial pathway of
FT apoptosis"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 142..187
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 150..230
FT /note="Interaction with PYHIN1 and necessary for
FT interaction with RFFL and RNF34"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT REGION 170..306
FT /note="Interaction with MTBP"
FT /evidence="ECO:0000250"
FT REGION 210..304
FT /note="ARF-binding"
FT REGION 211..237
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 223..232
FT /note="Interaction with USP7"
FT /evidence="ECO:0000250"
FT REGION 242..331
FT /note="Region II"
FT REGION 253..275
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 276..491
FT /note="Necessary for interaction with USP2"
FT /evidence="ECO:0000250"
FT REGION 333..402
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 409..428
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 179..185
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000255"
FT MOTIF 190..202
FT /note="Nuclear export signal"
FT MOTIF 466..473
FT /note="Nucleolar localization signal"
FT /evidence="ECO:0000255"
FT COMPBIAS 145..161
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 162..187
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 211..225
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 253..271
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 333..379
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 380..402
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 409..425
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 166
FT /note="Phosphoserine; by SGK1"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 190
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P23804"
FT MOD_RES 240
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 242
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 260
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 262
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 386
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 395
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 407
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 419
FT /note="Phosphothreonine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 425
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
FT MOD_RES 429
FT /note="Phosphoserine; by ATM"
FT /evidence="ECO:0000250|UniProtKB:Q00987"
SQ SEQUENCE 491 AA; 55279 MW; 641E033D5C1DEC39 CRC64;
MCNTNMSVST DGAVSTSQIP ASEQETLVRP KPLLLKLLKS VGAQKDTYTM KEVIFYLGQY
IMTKRLYDEK QQHIVYCSND LLGDLFGVPS FSVKEHRKIY TMIYRNLVVV SQQEPSDSGT
SVSENRCHLE GGSNQKDLVQ ELQEEKPSSS DMVSRPSTSS RRRAVSETEE NSDELPGERQ
RKRHKSDNIS LSFDESLALC VIREICCERS SSSESTGTPS NPDLDAGVSE HSGDWLDQDS
VSDQFSVEFE VESLDSEDYS LSEEGQELSD EDDEVYRVTV YQAGESDTDS FEEDPEISLA
DYWKCTSCNE MNPPLPPHCN RCWALRENWL PEDKGKDKGN MSEKAKLGDS MQEDEGFDVP
DCKKSTVSDS RESCVEENDD KITQASLSQE SEDYSQPSTS NSIIYSSQED VKEFEREETQ
DKEESMESSF PLNAIEPCVI CQGRPKNGCI VHGKTGHLMA CFTCAKKLKK RNKPCPVCRQ
PIQMIVLTYF P
