| IED ID | IndEnz0002012922 |
| Enzyme Type ID | protease012922 |
| Protein Name |
Cellular tumor antigen p53 Tumor suppressor p53 |
| Gene Name | Tp53 P53 Trp53 |
| Organism | Mus musculus (Mouse) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MTAMEESQSDISLELPLSQETFSGLWKLLPPEDILPSPHCMDDLLLPQDVEEFFEGPSEALRVSGAPAAQDPVTETPGPVAPAPATPWPLSSFVPSQKTYQGNYGFHLGFLQSGTAKSVMCTYSPPLNKLFCQLAKTCPVQLWVSATPPAGSRVRAMAIYKKSQHMTEVVRRCPHHERCSDGDGLAPPQHLIRVEGNLYPEYLEDRQTFRHSVVVPYEPPEAGSEYTTIHYKYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRDSFEVRVCACPGRDRRTEEENFRKKEVLCPELPPGSAKRALPTCTSASPPQKKKPLDGEYFTLKIRGRKRFEMFRELNEALELKDAHATEESGDSRAHSSYLKTKKGQSTSRHKKTMVKKVGPDSD |
| Enzyme Length | 390 |
| Uniprot Accession Number | P02340 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | DNA_BIND 99..289; /evidence=ECO:0000250 |
| EC Number | |
| Enzyme Function | FUNCTION: Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (By similarity). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (By similarity). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression (By similarity). Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis, but seems to have to effect on cell-cycle regulation. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492). {ECO:0000250|UniProtKB:P04637, ECO:0000269|PubMed:19556538, ECO:0000269|PubMed:20673990, ECO:0000269|PubMed:22726440, ECO:0000269|PubMed:24051492}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (12); Chain (1); Compositional bias (1); Cross-link (4); DNA binding (1); Helix (6); Metal binding (4); Modified residue (25); Motif (3); Natural variant (3); Region (14); Sequence conflict (2); Site (1); Turn (4) |
| Keywords | 3D-structure;Acetylation;Activator;Apoptosis;Biological rhythms;Cell cycle;Cytoplasm;Cytoskeleton;DNA-binding;Disease variant;Endoplasmic reticulum;Isopeptide bond;Metal-binding;Methylation;Mitochondrion;Necrosis;Nucleus;Phosphoprotein;Reference proteome;Repressor;Transcription;Transcription regulation;Tumor suppressor;Ubl conjugation;Zinc |
| Interact With | P97302; B2RWS6; P23804; P23804-1; Q9QUR7; P54099; Q99KR7; O08586; Q61466; P09671; Q64127; P62991; Q07817-1; P03070 |
| Induction | INDUCTION: Expressed in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain with a peak seen at ZT8. {ECO:0000269|PubMed:24051492}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P04637}. Nucleus {ECO:0000250|UniProtKB:P04637}. Nucleus, PML body {ECO:0000250|UniProtKB:P04637}. Endoplasmic reticulum {ECO:0000250|UniProtKB:P04637}. Mitochondrion matrix {ECO:0000250|UniProtKB:P04637}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:P04637}. Note=Interaction with BANP promotes nuclear localization. Recruited into PML bodies together with CHEK2. Translocates to mitochondria upon oxidative stress. Translocates to mitochondria in response to mitomycin C treatment (By similarity). {ECO:0000250|UniProtKB:P04637}. |
| Modified Residue | MOD_RES 12; /note="Phosphoserine; by HIPK4"; /evidence="ECO:0000269|PubMed:18022393"; MOD_RES 18; /note="Phosphoserine; by CDK5, PRPK, AMPK, NUAK1 and ATM"; /evidence="ECO:0000269|PubMed:15195100"; MOD_RES 21; /note="Phosphothreonine; by CK1, VRK1 and VRK2"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 23; /note="Phosphoserine; by CHEK2, CK1 and PLK3"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 37; /note="Phosphoserine; by MAPKAPK5"; /evidence="ECO:0000269|PubMed:17254968"; MOD_RES 117; /note="N6-acetyllysine; by KAT6A"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 180; /note="Phosphoserine; by AURKB"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 266; /note="Phosphoserine; by AURKB"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 281; /note="Phosphothreonine; by AURKB"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 302; /note="N6-acetyllysine"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 312; /note="Phosphoserine; by AURKA, CDK1 and CDK2"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 318; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:23806337"; MOD_RES 330; /note="Omega-N-methylarginine"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 332; /note="Symmetric dimethylarginine"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 334; /note="Symmetric dimethylarginine"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 367; /note="N6,N6-dimethyllysine; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 367; /note="N6-methyllysine; by SMYD2; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 369; /note="N6-methyllysine; by SETD7"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 370; /note="N6,N6-dimethyllysine; by EHMT1 and EHMT2; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 370; /note="N6-acetyllysine; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 378; /note="N6-acetyllysine"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 379; /note="N6,N6-dimethyllysine; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 379; /note="N6-acetyllysine; by KAT6A; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 379; /note="N6-methyllysine; by KMT5A; alternate"; /evidence="ECO:0000250|UniProtKB:P04637"; MOD_RES 389; /note="Phosphoserine; by CK2, CDK2 and NUAK1"; /evidence="ECO:0000250|UniProtKB:P04637" |
| Post Translational Modification | PTM: Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylation at Ser-12 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-21 by VRK1. Phosphorylated on Ser-23 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-23 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Probably phosphorylated on by CDK7 in a CAK complex in response to DNA damage. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-18 leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes (By similarity). Phosphorylated on Ser-389 following UV but not gamma irradiation. Phosphorylated by HIPK1. Phosphorylation at Ser-18 is required for interaction with DDX3X and gamma-tubulin (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P04637, ECO:0000269|PubMed:12702766, ECO:0000269|PubMed:15195100, ECO:0000269|PubMed:17254968, ECO:0000269|PubMed:18022393, ECO:0000269|PubMed:19556538, ECO:0000269|PubMed:2145148, ECO:0000269|PubMed:3006031}.; PTM: Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation. Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. Ubiquitinated by MKRN1 at Lys-288 and Lys-289, which leads to proteasomal degradation. Deubiquitinated by USP10, leading to stabilize it. Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation. Ubiquitination by TOPORS induces degradation. Deubiquitination by USP7, leading to stabilize it. Ubiquitinated by COP1, which leads to proteasomal degradation (By similarity). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (PubMed:24240685). {ECO:0000250|UniProtKB:P04637, ECO:0000269|PubMed:24240685, ECO:0000269|PubMed:25732823}.; PTM: Monomethylated at Lys-369 by SETD7, leading to stabilization and increased transcriptional activation. Monomethylated at Lys-367 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity. Lys-369 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-367. Dimethylated at Lys-370 by EHMT1 and EHMT2. Monomethylated at Lys-379 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Demethylation of dimethylated Lys-367 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (By similarity). Monomethylated at Arg-330 and dimethylated at Arg-332 and Arg-334 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (By similarity). Polyubiquitinated by MUL1 at Lys-27 which leads to proteasomal degradation (By similarity). {ECO:0000250|UniProtKB:P04637}.; PTM: Sumoylated with SUMO1. Sumoylated at Lys-383 by UBC9 (By similarity). {ECO:0000250}.; PTM: Acetylated. Acetylation by CREBBP enhances transcriptional activity. Acetylation by EP300. Deacetylation by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner. {ECO:0000250|UniProtKB:P04637}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (8) |
| Cross Reference PDB | 1HU8; 2GEQ; 2IOI; 2IOM; 2IOO; 2P52; 3EXJ; 3EXL; |
| Mapped Pubmed ID | !!!TOLONGITDOESNOTFITINEXCELL,NOTREPRESENTABLEINEXCELL!!!; |
| Motif | MOTIF 302..318; /note=Bipartite nuclear localization signal; /evidence=ECO:0000250; MOTIF 336..347; /note=Nuclear export signal; /evidence=ECO:0000250; MOTIF 367..369; /note=[KR]-[STA]-K motif |
| Gene Encoded By | |
| Mass | 43,458 |
| Kinetics | |
| Metal Binding | METAL 173; /note=Zinc; METAL 176; /note=Zinc; METAL 235; /note=Zinc; METAL 239; /note=Zinc |
| Rhea ID | |
| Cross Reference Brenda |