| IED ID | IndEnz0002006122 |
| Enzyme Type ID | protease006122 |
| Protein Name |
Neurogenic locus notch homolog protein 1 Notch 1 Cleaved into: Notch 1 extracellular truncation NEXT ; Notch 1 intracellular domain NICD |
| Gene Name | Notch1 |
| Organism | Rattus norvegicus (Rat) |
| 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 Rattus Rattus norvegicus (Rat) |
| Enzyme Sequence | MPRLLAPLLCLTLLPALAARGLRCSQPSGTCLNGGRCEVANGTEACVCSGAFVGQRCQDPSPCLSTPCKNAGTCYVVDHGGIVDYACSCPLGFSGPLCLTPLANACLANPCRNGGTCDLLTLTEYKCRCPPGWSGKSCQQADPCASNPCANGGQCLPFESSYICGCPPGFHGPTCRQDVNECSQNPGLCRHGGTCHNEIGSYRCACRATHTGPHCELPYVPCSPSPCQNGGTCRPTGDTTHECACLPGFAGQNCEENVDDCPGNNCKNGGACVDGVNTYNCRCPPEWTGQYCTEDVDECQLMPNACQNGGTCHNSHGGYNCVCVNGWTGEDCSENIDDCASAACFQGATCHDRVASFYCECPHGRTGLLCHLNDACISNPCNEGSNCDTNPVNGKAICTCPSGYTGPACSQDVDECALGANPCEHAGKCLNTLGSFECQCLQGYTGPRCEIDVNECISNPCQNDATCLDQIGEFQCICMPGYEGVYCEINTDECASSPCLHNGRCVDKINEFLCQCPKGFSGHLCQYDVDECASTPCKNGAKCLDGPNTYTCVCTEGYTGTHCEVDIDECDPDPCHYGLCKDGVATFTCLCQPGYTGHHCETNINECHSQPCRHGGTCQDRDNYYLCLCLKGTTGPNCEINLDDCASNPCDSGTCLDKIDGYECACEPGYTGSMCNVNIDECAGSPCHNGGTCEDGIAGFTCRCPEGYHDPTCLSEVNECNSNPCIHGACRDGLNGYKCDCAPGWSGTNCDINNNECESNPCVNGGTCKDMTSGYVCTCREGFSGPNCQTNINECASNPCLNQGTCIDDVAGYKCNCPLPYTGATCEVVLAPCATSPCKNSGVCKESEDYESFSCVCPTGWQGQTCEIDINECVKSPCRHGASCQNTNGSYRCLCQAGYTGRNCESDIDDCRPNPCHNGGSCTDGVNAAFCDCLPGFQGAFCEEDINECASNPCQNGANCTDCVDSYTCTCPTGFNGIHCENNTPDCTESSCFNGGTCVDGINSFTCLCPPGFTGSYCQYDVNECDSRPCLHGGTCQDSYGTYKCTCPQGYTGLNCQNLVRWCDSAPCKNGGKCWQTNTQYHCECRSGWTGFNCDVLSVSCEVAAQKRGIDVTLLCQHGGLCVDEEDKHYCHCQAGYTGSYCEDEVDECSPNPCQNGATCTDYLGGFSCKCVAGYHGSNCSEEINECLSQPCQNGGTCIDLTNTYKCSCPRGTQGVHCEINVDDCHPPLDPASRSPKCFNNGTCVDQVGGYTCTCPPGFVGERCEGDVNECLSNPCDPRGTQNCVQRVNDFHCECRAGHTGRRCESVINGCRGKPCRNGGVCAVASNTARGFICRCPAGFEGATCENDARTCGSLRCLNGGTCISGPRSPTCLCLGSFTGPECQFPASSPCVGSNPCYNQGTCEPTSESPFYRCLCPAKFNGLLCHILDYSFTGGAGRDIPPPQIEEACELPECQEDAGNKVCNLQCNNHACGWDGGDCSLNFNDPWKNCTQSLQCWKYFSDGHCDSQCNSAGCLFDGFDCQLTEGQCNPLYDQYCKDHFSDGHCDQGCNSAECEWDGLDCAEHVPERLAAGTLVLVVLLPPDQLRNNSFHFLRELSHVLHTNVVFKRDAQGQQMIFPYYGREEELRKHPIKRSAVGWATTSLLPGTNGGRQRRELDPMDIHGSIVYLEIDNRQCVQSSSQCFQSATDVAAFLGALASLGSLNIPYKIEAVKSETVEPPLPSQLHLMYVAAAAFVLLFFVGCGVLLSRKRRRQHGQLWFPEGFKVSEASKKKRREPLGEDSVGLKPLKNASDGALMDDNQNEWGDEDLETKKFRFEEPVVLPDLDDQTDHRQWTQQHLDAADLRVSAMAPTPPQGEVDADCMDVNVRGPDGFTPLMIASCSGGGLETGNSEEEEDAPAVISDFIYQGASLHNQTDRTGETALHLAARYSRSDAAKRLLEASADANIQDNMGRTPLHAAVSADAQGVFQILLRNRATDLDARMHDGTTPLILAARLAVEGMLEDLINSHADVNAVDDLGKSALHWAAAVNNVDAAVVLLKNGANKDMQNNKEETPLFLAAREGSYETAKVLLDHFANRDITDHMDRLPRDIAQERMHHDIVRLLDEYNLVRSPQLHGTALGGTPTLSPTLCSPNGYLGNLKSATQGKKARKPSTKGLACSSKEAKDLKARRKKSQDGKGCLLDSSSMLSPVDSLESPHGYLSDVASPPLLPSPFQQSPSMPLSHLPGMPDTHLGISHLNVAAKPEMAALAGGSRLAFEPPPPRLSHLPVASSASTVLSTNGTGAMNFTVGAPASLNGQCEWLPRLQNGMVPSQYNPLRPGVTPGTLSTQAAGLQHGMMGPIHSSLSTNTLSPIIYQGLPNTRLATQPHLVQTQQVQPQNLQIQPQNLQPPSQPHLSVSSAANGHLGRSFLSGEPSQADVQPLGPSSLPVHTILPQESQALPTSLPSSMVPPMTTTQFLTPPSQHSYSSSPVDNTPSHQLQVPEHPFLTPSPESPDQWSSSSPHSNISDWSEGISSPPTSMPSQITHIPEAFK |
| Enzyme Length | 2531 |
| Uniprot Accession Number | Q07008 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | FUNCTION: Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination (By similarity). Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus (By similarity). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (By similarity). Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus (By similarity). Important for follicular differentiation and possibly cell fate selection within the follicle (By similarity). During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia (PubMed:11182080). Represses neuronal and myogenic differentiation (By similarity). May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation (By similarity). May be involved in mesoderm development, somite formation and neurogenesis (By similarity). May enhance HIF1A function by sequestering HIF1AN away from HIF1A (By similarity). Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury (By similarity). Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (By similarity). {ECO:0000250|UniProtKB:Q01705, ECO:0000269|PubMed:11182080}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (18); Chain (3); Compositional bias (4); Cross-link (1); Disulfide bond (116); Domain (36); Glycosylation (49); Helix (2); Metal binding (16); Modified residue (3); Region (9); Repeat (8); Sequence conflict (9); Signal peptide (1); Site (3); Topological domain (2); Transmembrane (1); Turn (6) |
| Keywords | 3D-structure;ANK repeat;Activator;Angiogenesis;Calcium;Cell membrane;Developmental protein;Differentiation;Disulfide bond;EGF-like domain;Glycoprotein;Hydroxylation;Isopeptide bond;Membrane;Metal-binding;Notch signaling pathway;Nucleus;Phosphoprotein;Receptor;Reference proteome;Repeat;Signal;Transcription;Transcription regulation;Transmembrane;Transmembrane helix;Ubl conjugation |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q01705}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:Q01705}.; SUBCELLULAR LOCATION: [Notch 1 intracellular domain]: Nucleus {ECO:0000250|UniProtKB:Q01705}. Note=Following proteolytical processing NICD is translocated to the nucleus. Nuclear location may require MEGF10. {ECO:0000250|UniProtKB:Q01705}. |
| Modified Residue | MOD_RES 1851; /note=Phosphothreonine; /evidence=ECO:0000250|UniProtKB:Q01705; MOD_RES 1945; /note=(3S)-3-hydroxyasparagine; by HIF1AN; /evidence=ECO:0000250; MOD_RES 2012; /note=(3S)-3-hydroxyasparagine; by HIF1AN; /evidence=ECO:0000250 |
| Post Translational Modification | PTM: Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2) to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane. {ECO:0000250|UniProtKB:Q01705}.; PTM: Phosphorylated. {ECO:0000250}.; PTM: O-glycosylated on the EGF-like domains. O-glucosylated at Ser-435 by KDELC1 and KDELC2 (By similarity). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (PubMed:25700513). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity). {ECO:0000250|UniProtKB:P46531, ECO:0000250|UniProtKB:Q01705, ECO:0000269|PubMed:25700513}.; PTM: Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1. Monoubiquitination at Lys-1749 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch. {ECO:0000250|UniProtKB:Q01705}.; PTM: Hydroxylated at Asn-1945 and Asn-2012 by HIF1AN. Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity). {ECO:0000250}. |
| Signal Peptide | SIGNAL 1..18; /evidence=ECO:0000255 |
| Structure 3D | X-ray crystallography (3) |
| Cross Reference PDB | 4XL1; 4XLW; 5UK5; |
| Mapped Pubmed ID | 11700865; 11971902; 12853432; 12876431; 15057910; 16048523; 18449946; 18781453; 18824567; 18942116; 19109527; 19378247; 19481784; 20056840; 20195794; 20951801; 22110751; 23583836; 24563863; 28254785; 7697721; |
| Motif | |
| Gene Encoded By | |
| Mass | 270,822 |
| Kinetics | |
| Metal Binding | METAL 432; /note="Calcium 1; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 435; /note="Calcium 1; via amide nitrogen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 452; /note="Calcium 2"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 453; /note="Calcium 2; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 455; /note="Calcium 2"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 469; /note="Calcium 2"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 470; /note="Calcium 2; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 490; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 491; /note="Calcium 3; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 493; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 507; /note="Calcium 3"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 508; /note="Calcium 3; via carbonyl oxygen"; /evidence="ECO:0000269|PubMed:25700513, ECO:0007744|PDB:4XL1"; METAL 1457; /note="Calcium 4; via carbonyl oxygen"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00525"; METAL 1460; /note="Calcium 4"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00525"; METAL 1475; /note="Calcium 4"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00525"; METAL 1478; /note="Calcium 4"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00525" |
| Rhea ID | |
| Cross Reference Brenda |