ID NOTC2_HUMAN Reviewed; 2471 AA. AC Q04721; Q5T3X7; Q99734; Q9H240; DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot. DT 03-APR-2007, sequence version 3. DT 27-MAR-2024, entry version 250. DE RecName: Full=Neurogenic locus notch homolog protein 2 {ECO:0000305}; DE Short=Notch 2; DE Short=hN2; DE Contains: DE RecName: Full=Notch 2 extracellular truncation; DE Short=N2ECD {ECO:0000303|PubMed:25985737}; DE Contains: DE RecName: Full=Notch 2 intracellular domain; DE Short=N2ICD {ECO:0000303|PubMed:25985737}; DE Flags: Precursor; GN Name=NOTCH2 {ECO:0000312|HGNC:HGNC:7882}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RA Blaumueller C.M., Mann R.S.; RT "Complete human notch 2 (hN2) cDNA sequence."; RL Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Mammary tumor; RA Correa R.G., Camargo A.A., Moreira E.S., Simpson A.J.G.; RT "Human Notch2, a novel member of cell-fate determining NOTCH family."; RL Submitted (OCT-2000) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 967-1229. RC TISSUE=T-cell; RA Lemasson I., Devaux C., Mesnard J.-M.; RT "Partial sequence of EGF-like repeat domain of human Notch2 mRNA."; RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1810-2447. RC TISSUE=Brain; RX PubMed=1303260; DOI=10.1038/ng1092-119; RA Stifani S., Blaumueller C.M., Redhead N.J., Hill R.E., RA Artavanis-Tsakonas S.; RT "Human homologs of a Drosophila enhancer of split gene product define a RT novel family of nuclear proteins."; RL Nat. Genet. 2:119-127(1992). RN [6] RP PROTEOLYTIC PROCESSING, AND SUBCELLULAR LOCATION. RX PubMed=9244302; DOI=10.1016/s0092-8674(00)80336-0; RA Blaumueller C.M., Qi H., Zagouras P., Artavanis-Tsakonas S.; RT "Intracellular cleavage of Notch leads to a heterodimeric receptor on the RT plasma membrane."; RL Cell 90:281-291(1997). RN [7] RP IDENTIFICATION OF LIGANDS. RX PubMed=10079256; DOI=10.1016/s0002-9440(10)65325-4; RA Gray G.E., Mann R.S., Mitsiadis E., Henrique D., Carcangiu M.-L., Banks A., RA Leiman J., Ward D., Ish-Horowitz D., Artavanis-Tsakonas S.; RT "Human ligands of the Notch receptor."; RL Am. J. Pathol. 154:785-794(1999). RN [8] RP INTERACTION WITH MAML1. RX PubMed=11101851; DOI=10.1038/82644; RA Wu L., Aster J.C., Blacklow S.C., Lake R., Artavanis-Tsakonas S., RA Griffin J.D.; RT "MAML1, a human homologue of Drosophila mastermind, is a transcriptional RT co-activator for NOTCH receptors."; RL Nat. Genet. 26:484-489(2000). RN [9] RP INTERACTION WITH MAML2 AND MAML3. RX PubMed=12370315; DOI=10.1128/mcb.22.21.7688-7700.2002; RA Wu L., Sun T., Kobayashi K., Gao P., Griffin J.D.; RT "Identification of a family of mastermind-like transcriptional coactivators RT for mammalian notch receptors."; RL Mol. Cell. Biol. 22:7688-7700(2002). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [11] RP INTERACTION WITH HIF1AN. RX PubMed=17573339; DOI=10.1074/jbc.m704102200; RA Coleman M.L., McDonough M.A., Hewitson K.S., Coles C., Mecinovic J., RA Edelmann M., Cook K.M., Cockman M.E., Lancaster D.E., Kessler B.M., RA Oldham N.J., Ratcliffe P.J., Schofield C.J.; RT "Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor RT inhibiting hypoxia-inducible factor."; RL J. Biol. Chem. 282:24027-24038(2007). RN [12] RP INTERACTION WITH MDK. RX PubMed=18469519; DOI=10.4161/cc.7.11.5952; RA Huang Y., Hoque M.O., Wu F., Trink B., Sidransky D., Ratovitski E.A.; RT "Midkine induces epithelial-mesenchymal transition through Notch2/Jak2- RT Stat3 signaling in human keratinocytes."; RL Cell Cycle 7:1613-1622(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1716; THR-1802; SER-1804; RP THR-1808; SER-1845; SER-2070; SER-2081 AND THR-2097, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP HYDROXYLATION BY HIF1AN. RX PubMed=18299578; DOI=10.1073/pnas.0711591105; RA Zheng X., Linke S., Dias J.M., Zheng X., Gradin K., Wallis T.P., RA Hamilton B.R., Gustafsson M., Ruas J.L., Wilkins S., Bilton R.L., RA Brismar K., Whitelaw M.L., Pereira T., Gorman J.J., Ericson J., Peet D.J., RA Lendahl U., Poellinger L.; RT "Interaction with factor inhibiting HIF-1 defines an additional mode of RT cross-coupling between the Notch and hypoxia signaling pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 105:3368-3373(2008). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1778 AND SER-1845, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1778, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [17] RP INVOLVEMENT IN HJCYS, AND VARIANTS HJCYS 2208-GLN--ALA-2471 DEL; RP 2223-GLN--ALA-2471 DEL AND 2360-GLN--ALA-2471 DEL. RX PubMed=21681853; DOI=10.1002/humu.21546; RG FORGE Canada Consortium; RA Majewski J., Schwartzentruber J.A., Caqueret A., Patry L., Marcadier J., RA Fryns J.P., Boycott K.M., Ste-Marie L.G., McKiernan F.E., Marik I., RA Van Esch H., Michaud J.L., Samuels M.E.; RT "Mutations in NOTCH2 in families with Hajdu-Cheney syndrome."; RL Hum. Mutat. 32:1114-1117(2011). RN [18] RP FUNCTION, INVOLVEMENT IN HJCYS, AND VARIANTS HJCYS 2285-GLN--ALA-2471 DEL; RP 2317-GLN--ALA-2471 DEL AND 2373-TYR--ALA-2471 DEL. RX PubMed=21378989; DOI=10.1038/ng.778; RA Isidor B., Lindenbaum P., Pichon O., Bezieau S., Dina C., Jacquemont S., RA Martin-Coignard D., Thauvin-Robinet C., Le Merrer M., Mandel J.L., RA David A., Faivre L., Cormier-Daire V., Redon R., Le Caignec C.; RT "Truncating mutations in the last exon of NOTCH2 cause a rare skeletal RT disorder with osteoporosis."; RL Nat. Genet. 43:306-308(2011). RN [19] RP FUNCTION, INVOLVEMENT IN HJCYS, TISSUE SPECIFICITY, AND VARIANTS HJCYS RP 2140-GLN--ALA-2471 DEL; 2208-GLN--ALA-2471 DEL; 2325-GLN--ALA-2471 DEL AND RP 2400-ARG--ALA-2471 DEL. RX PubMed=21378985; DOI=10.1038/ng.779; RA Simpson M.A., Irving M.D., Asilmaz E., Gray M.J., Dafou D., Elmslie F.V., RA Mansour S., Holder S.E., Brain C.E., Burton B.K., Kim K.H., Pauli R.M., RA Aftimos S., Stewart H., Kim C.A., Holder-Espinasse M., Robertson S.P., RA Drake W.M., Trembath R.C.; RT "Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and RT progressive bone loss."; RL Nat. Genet. 43:303-305(2011). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1778, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [21] RP FUNCTION, INTERACTION WITH TCIM, AND SUBCELLULAR LOCATION. RX PubMed=25985737; DOI=10.1038/ncomms8122; RA Zhu P., Wang Y., Du Y., He L., Huang G., Zhang G., Yan X., Fan Z.; RT "C8orf4 negatively regulates self-renewal of liver cancer stem cells via RT suppression of NOTCH2 signalling."; RL Nat. Commun. 6:7122-7122(2015). RN [22] RP FUNCTION, PHOSPHORYLATION BY GSK3, UBIQUITINATION, INTERACTION WITH CUL1; RP SKP1; RBX1 AND FBW7, MUTAGENESIS OF THR-2416, AND CHARACTERIZATION OF RP VARIANT HJCYS 2317-GLN--ALA-2471 DEL. RX PubMed=29149593; DOI=10.1016/j.molcel.2017.10.018; RA Fukushima H., Shimizu K., Watahiki A., Hoshikawa S., Kosho T., Oba D., RA Sakano S., Arakaki M., Yamada A., Nagashima K., Okabe K., Fukumoto S., RA Jimi E., Bigas A., Nakayama K.I., Nakayama K., Aoki Y., Wei W., Inuzuka H.; RT "NOTCH2 Hajdu-Cheney mutations escape SCFFBW7-dependent proteolysis to RT promote osteoporosis."; RL Mol. Cell 68:645-658(2017). RN [23] RP INTERACTION WITH NOTCH2NLA; NOTCH2NLB AND NOTCH2NLC. RX PubMed=29856954; DOI=10.1016/j.cell.2018.03.051; RA Fiddes I.T., Lodewijk G.A., Mooring M., Bosworth C.M., Ewing A.D., RA Mantalas G.L., Novak A.M., van den Bout A., Bishara A., Rosenkrantz J.L., RA Lorig-Roach R., Field A.R., Haeussler M., Russo L., Bhaduri A., RA Nowakowski T.J., Pollen A.A., Dougherty M.L., Nuttle X., Addor M.C., RA Zwolinski S., Katzman S., Kriegstein A., Eichler E.E., Salama S.R., RA Jacobs F.M.J., Haussler D.; RT "Human-specific NOTCH2NL genes affect Notch signaling and cortical RT neurogenesis."; RL Cell 173:1356-1369(2018). RN [24] RP SUBCELLULAR LOCATION, AND INTERACTION WITH MINAR1. RX PubMed=29329397; DOI=10.1093/jmcb/mjy002; RA Ho R.X., Meyer R.D., Chandler K.B., Ersoy E., Park M., Bondzie P.A., RA Rahimi N., Xu H., Costello C.E., Rahimi N.; RT "MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast RT cancer growth."; RL J. Mol. Cell Biol. 10:195-204(2018). RN [25] RP INTERACTION WITH MINAR2. RX PubMed=32954300; DOI=10.1093/braincomms/fcaa047; RA Ho R.X., Amraei R., De La Cena K.O.C., Sutherland E.G., Mortazavi F., RA Stein T., Chitalia V., Rahimi N.; RT "Loss of MINAR2 impairs motor function and causes Parkinson's disease-like RT symptoms in mice."; RL Brain Commun. 2:fcaa047-fcaa047(2020). RN [26] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1426-1677, AND DISULFIDE BONDS. RX PubMed=17401372; DOI=10.1038/nsmb1227; RA Gordon W.R., Vardar-Ulu D., Histen G., Sanchez-Irizarry C., Aster J.C., RA Blacklow S.C.; RT "Structural basis for autoinhibition of Notch."; RL Nat. Struct. Mol. Biol. 14:295-300(2007). RN [27] RP VARIANT ALGS2 TYR-444. RX PubMed=16773578; DOI=10.1086/505332; RA McDaniell R., Warthen D.M., Sanchez-Lara P.A., Pai A., Krantz I.D., RA Piccoli D.A., Spinner N.B.; RT "NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the RT notch signaling pathway."; RL Am. J. Hum. Genet. 79:169-173(2006). RN [28] RP VARIANT HJCYS 2400-ARG--ALA-2471 DEL. RX PubMed=21793104; DOI=10.1002/humu.21563; RA Isidor B., Le Merrer M., Exner G.U., Pichon O., Thierry G., RA Guiochon-Mantel A., David A., Cormier-Daire V., Le Caignec C.; RT "Serpentine fibula-polycystic kidney syndrome caused by truncating RT mutations in NOTCH2."; RL Hum. Mutat. 32:1239-1242(2011). RN [29] RP VARIANTS HJCYS 2299-GLU--ALA-2471 DEL AND 2389-GLN--ALA-2471 DEL. RX PubMed=21712856; DOI=10.1038/ejhg.2011.125; RA Gray M.J., Kim C.A., Bertola D.R., Arantes P.R., Stewart H., Simpson M.A., RA Irving M.D., Robertson S.P.; RT "Serpentine fibula polycystic kidney syndrome is part of the phenotypic RT spectrum of Hajdu-Cheney syndrome."; RL Eur. J. Hum. Genet. 20:122-124(2012). RN [30] RP VARIANTS HJCYS 2196-GLN--ALA-2471 DEL AND 2400-ARG--ALA-2471 DEL. RX PubMed=23389697; DOI=10.1007/s00198-013-2298-5; RA Zhao W., Petit E., Gafni R.I., Collins M.T., Robey P.G., Seton M., RA Miller K.K., Mannstadt M.; RT "Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome."; RL Osteoporos. Int. 24:2275-2281(2013). CC -!- FUNCTION: Functions as a receptor for membrane-bound ligands Jagged-1 CC (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate CC determination. Upon ligand activation through the released notch CC intracellular domain (NICD) it forms a transcriptional activator CC complex with RBPJ/RBPSUH and activates genes of the enhancer of split CC locus (PubMed:21378985, PubMed:21378989). Affects the implementation of CC differentiation, proliferation and apoptotic programs (By similarity). CC Involved in bone remodeling and homeostasis. In collaboration with CC RELA/p65 enhances NFATc1 promoter activity and positively regulates CC RANKL-induced osteoclast differentiation (PubMed:29149593). Positively CC regulates self-renewal of liver cancer cells (PubMed:25985737). CC {ECO:0000250|UniProtKB:O35516, ECO:0000269|PubMed:21378985, CC ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:25985737, CC ECO:0000269|PubMed:29149593}. CC -!- SUBUNIT: Heterodimer of a C-terminal fragment N(TM) and an N-terminal CC fragment N(EC) which are probably linked by disulfide bonds (By CC similarity). Interacts with MAML1, MAML2 and MAML3 which act as CC transcriptional coactivators for NOTCH2. Interacts with RELA/p65 (By CC similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with CC TCIM, the interaction inhibits the nuclear translocation of NOTCH2 CC N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that CC are SCF(FBXW7) E3 ubiquitin-protein ligase complex components CC (PubMed:29149593). Interacts with MINAR1; this interaction increases CC MINAR1 stability and function (PubMed:29329397). Interacts with CC NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance CC Notch signaling pathway in a non-cell-autonomous manner CC (PubMed:29856954). Interacts with MDK; this interaction mediates a CC nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 CC signaling leading to interaction between HES1 and STAT3 CC (PubMed:18469519). Interacts with MINAR2 (PubMed:32954300). CC {ECO:0000250, ECO:0000269|PubMed:11101851, ECO:0000269|PubMed:12370315, CC ECO:0000269|PubMed:17573339, ECO:0000269|PubMed:18469519, CC ECO:0000269|PubMed:25985737, ECO:0000269|PubMed:29149593, CC ECO:0000269|PubMed:29329397, ECO:0000269|PubMed:29856954, CC ECO:0000269|PubMed:32954300}. CC -!- SUBCELLULAR LOCATION: [Notch 2 extracellular truncation]: Cell membrane CC {ECO:0000269|PubMed:29329397, ECO:0000269|PubMed:9244302}; Single-pass CC type I membrane protein {ECO:0000269|PubMed:9244302}. CC -!- SUBCELLULAR LOCATION: [Notch 2 intracellular domain]: Nucleus CC {ECO:0000269|PubMed:25985737}. Cytoplasm {ECO:0000269|PubMed:25985737}. CC Note=Following proteolytical processing NICD is translocated to the CC nucleus. Retained at the cytoplasm by TCIM (PubMed:25985737). CC {ECO:0000269|PubMed:25985737}. CC -!- TISSUE SPECIFICITY: Expressed in the brain, heart, kidney, lung, CC skeletal muscle and liver. Ubiquitously expressed in the embryo. CC {ECO:0000269|PubMed:21378985}. CC -!- PTM: Synthesized in the endoplasmic reticulum as an inactive form which CC is proteolytically cleaved by a furin-like convertase in the trans- CC Golgi network before it reaches the plasma membrane to yield an active, CC ligand-accessible form (By similarity). Cleavage results in a C- CC terminal fragment N(TM) and a N-terminal fragment N(EC) (By CC similarity). Following ligand binding, it is cleaved by TNF-alpha CC converting enzyme (TACE) to yield a membrane-associated intermediate CC fragment called notch extracellular truncation (NEXT) (By similarity). CC This fragment is then cleaved by presenilin dependent gamma-secretase CC to release a notch-derived peptide containing the intracellular domain CC (NICD) from the membrane (By similarity). CC {ECO:0000250|UniProtKB:O35516, ECO:0000250|UniProtKB:Q01705}. CC -!- PTM: Hydroxylated by HIF1AN. {ECO:0000269|PubMed:18299578}. CC -!- PTM: Can be either O-glucosylated or O-xylosylated at Ser-613 by CC POGLUT1. {ECO:0000250|UniProtKB:O35516}. CC -!- PTM: Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary CC for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the CC ubiquitin proteasome pathway. {ECO:0000269|PubMed:29149593}. CC -!- DISEASE: Alagille syndrome 2 (ALGS2) [MIM:610205]: A form of Alagille CC syndrome, an autosomal dominant multisystem disorder. It is clinically CC defined by hepatic bile duct paucity and cholestasis in association CC with cardiac, skeletal, and ophthalmologic manifestations. There are CC characteristic facial features and less frequent clinical involvement CC of the renal and vascular systems. {ECO:0000269|PubMed:16773578}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Hajdu-Cheney syndrome (HJCYS) [MIM:102500]: A rare, autosomal CC dominant skeletal disorder characterized by the association of facial CC anomalies, acro-osteolysis, general osteoporosis, insufficient CC ossification of the skull, and periodontal disease (premature loss of CC permanent teeth). Other features include cleft palate, congenital heart CC defects, polycystic kidneys, orthopedic problems and anomalies of the CC genitalia, intestines and eyes. {ECO:0000269|PubMed:21378985, CC ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:21681853, CC ECO:0000269|PubMed:21712856, ECO:0000269|PubMed:21793104, CC ECO:0000269|PubMed:23389697, ECO:0000269|PubMed:29149593}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. NOTCH2 nonsense and frameshift mutations associated with Hajdu- CC Cheney syndrome cluster to the last coding exon of the gene. Mutant CC mRNA products escape nonsense-mediated decay and the resulting CC truncated NOTCH2 proteins act in a gain-of-function manner CC (PubMed:21378989). The pathological mechanism at cellular level CC involves disruption of a high affinity degron recognized by FBXW7 at CC the C-terminus, loss of interaction with FBXW7, reduced ubiquitination CC and degradation, and increased NOTCH2 levels. Bone marrow cells derived CC from HJCYS patients have an enhanced capacity of osteoclastogenesis due CC to sustained NOTCH2 activity (PubMed:29149593). CC {ECO:0000269|PubMed:21378989, ECO:0000269|PubMed:29149593}. CC -!- SIMILARITY: Belongs to the NOTCH family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41556/NOTCH2"; 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; AF308601; AAA36377.2; -; mRNA. DR EMBL; AF315356; AAG37073.1; -; mRNA. DR EMBL; AL359752; CAI18974.1; -; Genomic_DNA. DR EMBL; AL512503; CAI18974.1; JOINED; Genomic_DNA. DR EMBL; AL596222; CAI18974.1; JOINED; Genomic_DNA. DR EMBL; AL512503; CAH72483.1; -; Genomic_DNA. DR EMBL; AL359752; CAH72483.1; JOINED; Genomic_DNA. DR EMBL; AL596222; CAH72483.1; JOINED; Genomic_DNA. DR EMBL; AL596222; CAH70182.1; -; Genomic_DNA. DR EMBL; AL359752; CAH70182.1; JOINED; Genomic_DNA. DR EMBL; AL512503; CAH70182.1; JOINED; Genomic_DNA. DR EMBL; U77493; AAB19224.1; -; mRNA. DR CCDS; CCDS908.1; -. DR RefSeq; NP_001186930.1; NM_001200001.1. DR RefSeq; NP_077719.2; NM_024408.3. DR PDB; 2OO4; X-ray; 2.00 A; A/B=1423-1677. DR PDB; 5MWB; X-ray; 1.86 A; A=414-532. DR PDBsum; 2OO4; -. DR PDBsum; 5MWB; -. DR AlphaFoldDB; Q04721; -. DR SMR; Q04721; -. DR BioGRID; 110915; 480. DR CORUM; Q04721; -. DR ELM; Q04721; -. DR IntAct; Q04721; 71. DR MINT; Q04721; -. DR STRING; 9606.ENSP00000256646; -. DR BindingDB; Q04721; -. DR ChEMBL; CHEMBL3407320; -. DR GuidetoPHARMACOLOGY; 2859; -. DR GlyConnect; 1553; 2 N-Linked glycans (1 site). DR GlyCosmos; Q04721; 11 sites, 4 glycans. DR GlyGen; Q04721; 17 sites, 2 N-linked glycans (1 site), 4 O-linked glycans (11 sites). DR iPTMnet; Q04721; -. DR PhosphoSitePlus; Q04721; -. DR SwissPalm; Q04721; -. DR BioMuta; NOTCH2; -. DR DMDM; 143811429; -. DR EPD; Q04721; -. DR jPOST; Q04721; -. DR MassIVE; Q04721; -. DR MaxQB; Q04721; -. DR PaxDb; 9606-ENSP00000256646; -. DR PeptideAtlas; Q04721; -. DR ProteomicsDB; 58265; -. DR Pumba; Q04721; -. DR ABCD; Q04721; 25 sequenced antibodies. DR Antibodypedia; 20208; 745 antibodies from 43 providers. DR DNASU; 4853; -. DR Ensembl; ENST00000256646.7; ENSP00000256646.2; ENSG00000134250.21. DR GeneID; 4853; -. DR KEGG; hsa:4853; -. DR MANE-Select; ENST00000256646.7; ENSP00000256646.2; NM_024408.4; NP_077719.2. DR UCSC; uc001eik.4; human. DR AGR; HGNC:7882; -. DR CTD; 4853; -. DR DisGeNET; 4853; -. DR GeneCards; NOTCH2; -. DR GeneReviews; NOTCH2; -. DR HGNC; HGNC:7882; NOTCH2. DR HPA; ENSG00000134250; Low tissue specificity. DR MalaCards; NOTCH2; -. DR MIM; 102500; phenotype. DR MIM; 600275; gene. DR MIM; 610205; phenotype. DR neXtProt; NX_Q04721; -. DR OpenTargets; ENSG00000134250; -. DR Orphanet; 261629; Alagille syndrome due to a NOTCH2 point mutation. DR Orphanet; 955; Hajdu-Cheney syndrome. DR PharmGKB; PA31684; -. DR VEuPathDB; HostDB:ENSG00000134250; -. DR eggNOG; KOG1217; Eukaryota. DR GeneTree; ENSGT00940000155030; -. DR HOGENOM; CLU_000576_0_0_1; -. DR InParanoid; Q04721; -. DR OMA; AHMSEPP; -. DR OrthoDB; 5473534at2759; -. DR PhylomeDB; Q04721; -. DR TreeFam; TF351641; -. DR PathwayCommons; Q04721; -. DR Reactome; R-HSA-1912399; Pre-NOTCH Processing in the Endoplasmic Reticulum. DR Reactome; R-HSA-1912408; Pre-NOTCH Transcription and Translation. DR Reactome; R-HSA-1912420; Pre-NOTCH Processing in Golgi. DR Reactome; R-HSA-2197563; NOTCH2 intracellular domain regulates transcription. DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus. DR Reactome; R-HSA-350054; Notch-HLH transcription pathway. DR Reactome; R-HSA-5083630; Defective LFNG causes SCDO3. DR Reactome; R-HSA-9013695; NOTCH4 Intracellular Domain Regulates Transcription. DR SignaLink; Q04721; -. DR SIGNOR; Q04721; -. DR BioGRID-ORCS; 4853; 13 hits in 1161 CRISPR screens. DR ChiTaRS; NOTCH2; human. DR EvolutionaryTrace; Q04721; -. DR GeneWiki; Notch-2; -. DR GenomeRNAi; 4853; -. DR Pharos; Q04721; Tchem. DR PRO; PR:Q04721; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; Q04721; Protein. DR Bgee; ENSG00000134250; Expressed in pigmented layer of retina and 205 other cell types or tissues. DR ExpressionAtlas; Q04721; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005929; C:cilium; IEA:Ensembl. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0043235; C:receptor complex; IDA:MGI. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; IDA:BHF-UCL. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:BHF-UCL. DR GO; GO:0019899; F:enzyme binding; IEA:Ensembl. DR GO; GO:0051059; F:NF-kappaB binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; NAS:UniProtKB. DR GO; GO:0009887; P:animal organ morphogenesis; IEP:UniProtKB. DR GO; GO:0006915; P:apoptotic process; TAS:UniProtKB. DR GO; GO:0060413; P:atrial septum morphogenesis; IMP:BHF-UCL. DR GO; GO:0003162; P:atrioventricular node development; NAS:BHF-UCL. DR GO; GO:0007411; P:axon guidance; IBA:GO_Central. DR GO; GO:0030509; P:BMP signaling pathway; IEA:Ensembl. DR GO; GO:0046849; P:bone remodeling; IMP:UniProtKB. DR GO; GO:0001709; P:cell fate determination; TAS:UniProtKB. DR GO; GO:0071228; P:cellular response to tumor cell; IDA:UniProtKB. DR GO; GO:1990705; P:cholangiocyte proliferation; IEA:Ensembl. DR GO; GO:0061073; P:ciliary body morphogenesis; IEA:Ensembl. DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl. DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl. DR GO; GO:0072104; P:glomerular capillary formation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0030097; P:hemopoiesis; TAS:UniProtKB. DR GO; GO:0072574; P:hepatocyte proliferation; IEA:Ensembl. DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IDA:UniProtKB. DR GO; GO:0035622; P:intrahepatic bile duct development; IEA:Ensembl. DR GO; GO:0070986; P:left/right axis specification; IEA:Ensembl. DR GO; GO:0002315; P:marginal zone B cell differentiation; ISS:UniProtKB. DR GO; GO:0002011; P:morphogenesis of an epithelial sheet; IEA:Ensembl. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl. DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl. DR GO; GO:0007399; P:nervous system development; NAS:UniProtKB. DR GO; GO:0007219; P:Notch signaling pathway; IDA:UniProtKB. DR GO; GO:0060674; P:placenta blood vessel development; IEA:Ensembl. DR GO; GO:0072015; P:podocyte development; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0030513; P:positive regulation of BMP signaling pathway; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0010838; P:positive regulation of keratinocyte proliferation; IDA:UniProtKB. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl. DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IDA:UniProtKB. DR GO; GO:0051152; P:positive regulation of smooth muscle cell differentiation; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0072014; P:proximal tubule development; IEA:Ensembl. DR GO; GO:0003184; P:pulmonary valve morphogenesis; IMP:BHF-UCL. DR GO; GO:2001204; P:regulation of osteoclast development; IMP:UniProtKB. DR GO; GO:0042060; P:wound healing; IEA:Ensembl. DR CDD; cd00054; EGF_CA; 27. DR CDD; cd21703; JMTM_Notch2; 1. DR Gene3D; 3.30.300.320; -; 1. DR Gene3D; 3.30.70.3310; -; 1. DR Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1. DR Gene3D; 2.10.25.10; Laminin; 35. DR IDEAL; IID00463; -. DR InterPro; IPR002110; Ankyrin_rpt. DR InterPro; IPR036770; Ankyrin_rpt-contain_sf. DR InterPro; IPR001881; EGF-like_Ca-bd_dom. DR InterPro; IPR013032; EGF-like_CS. DR InterPro; IPR000742; EGF-like_dom. DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site. DR InterPro; IPR018097; EGF_Ca-bd_CS. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR008297; Notch. DR InterPro; IPR035993; Notch-like_dom_sf. DR InterPro; IPR022336; Notch_2. DR InterPro; IPR024600; Notch_C. DR InterPro; IPR000800; Notch_dom. DR InterPro; IPR010660; Notch_NOD_dom. DR InterPro; IPR011656; Notch_NODP_dom. DR PANTHER; PTHR24044; NOTCH LIGAND FAMILY MEMBER; 1. DR PANTHER; PTHR24044:SF505; NOTCH RECEPTOR 2; 1. DR Pfam; PF00023; Ank; 2. DR Pfam; PF12796; Ank_2; 1. DR Pfam; PF00008; EGF; 20. DR Pfam; PF07645; EGF_CA; 4. DR Pfam; PF12661; hEGF; 7. DR Pfam; PF06816; NOD; 1. DR Pfam; PF07684; NODP; 1. DR Pfam; PF00066; Notch; 3. DR PIRSF; PIRSF002279; Notch; 1. DR PRINTS; PR00010; EGFBLOOD. DR PRINTS; PR01452; LNOTCHREPEAT. DR PRINTS; PR01983; NOTCH. DR PRINTS; PR01985; NOTCH2. DR SMART; SM00248; ANK; 6. DR SMART; SM01334; DUF3454; 1. DR SMART; SM00181; EGF; 36. DR SMART; SM00179; EGF_CA; 34. DR SMART; SM00004; NL; 3. DR SMART; SM01338; NOD; 1. DR SMART; SM01339; NODP; 1. DR SUPFAM; SSF48403; Ankyrin repeat; 1. DR SUPFAM; SSF57196; EGF/Laminin; 14. DR SUPFAM; SSF57184; Growth factor receptor domain; 6. DR SUPFAM; SSF90193; Notch domain; 2. DR PROSITE; PS50297; ANK_REP_REGION; 1. DR PROSITE; PS50088; ANK_REPEAT; 4. DR PROSITE; PS00010; ASX_HYDROXYL; 22. DR PROSITE; PS00022; EGF_1; 34. DR PROSITE; PS01186; EGF_2; 29. DR PROSITE; PS50026; EGF_3; 35. DR PROSITE; PS01187; EGF_CA; 22. DR PROSITE; PS50258; LNR; 3. DR Genevisible; Q04721; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; ANK repeat; Cell membrane; Cytoplasm; KW Developmental protein; Differentiation; Disease variant; Disulfide bond; KW EGF-like domain; Glycoprotein; Membrane; Notch signaling pathway; Nucleus; KW Phosphoprotein; Receptor; Reference proteome; Repeat; Signal; KW Transcription; Transcription regulation; Transmembrane; KW Transmembrane helix; Ubl conjugation. FT SIGNAL 1..25 FT /evidence="ECO:0000255" FT CHAIN 26..2471 FT /note="Neurogenic locus notch homolog protein 2" FT /id="PRO_0000007683" FT CHAIN 1666..2471 FT /note="Notch 2 extracellular truncation" FT /evidence="ECO:0000250|UniProtKB:Q01705" FT /id="PRO_0000007684" FT CHAIN 1697..2471 FT /note="Notch 2 intracellular domain" FT /evidence="ECO:0000250|UniProtKB:O35516" FT /id="PRO_0000007685" FT TOPO_DOM 26..1677 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 1678..1698 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1699..2471 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 26..63 FT /note="EGF-like 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 64..102 FT /note="EGF-like 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 105..143 FT /note="EGF-like 3" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 144..180 FT /note="EGF-like 4" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 182..219 FT /note="EGF-like 5; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 221..258 FT /note="EGF-like 6" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 260..296 FT /note="EGF-like 7; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 298..336 FT /note="EGF-like 8; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 338..374 FT /note="EGF-like 9; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 375..413 FT /note="EGF-like 10" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 415..454 FT /note="EGF-like 11; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 456..492 FT /note="EGF-like 12; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 494..530 FT /note="EGF-like 13; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 532..568 FT /note="EGF-like 14; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 570..605 FT /note="EGF-like 15; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 607..643 FT /note="EGF-like 16; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 645..680 FT /note="EGF-like 17; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 682..718 FT /note="EGF-like 18; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 720..755 FT /note="EGF-like 19" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 757..793 FT /note="EGF-like 20; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 795..831 FT /note="EGF-like 21; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 833..871 FT /note="EGF-like 22" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 873..909 FT /note="EGF-like 23; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 911..947 FT /note="EGF-like 24; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 949..985 FT /note="EGF-like 25; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 987..1023 FT /note="EGF-like 26; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1025..1061 FT /note="EGF-like 27; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1063..1099 FT /note="EGF-like 28" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1101..1147 FT /note="EGF-like 29" FT /evidence="ECO:0000305" FT DOMAIN 1149..1185 FT /note="EGF-like 30; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1187..1223 FT /note="EGF-like 31; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1225..1262 FT /note="EGF-like 32; calcium-binding" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1264..1302 FT /note="EGF-like 33" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1304..1343 FT /note="EGF-like 34" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 1374..1412 FT /note="EGF-like 35" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT REPEAT 1425..1465 FT /note="LNR 1" FT REPEAT 1466..1502 FT /note="LNR 2" FT REPEAT 1503..1544 FT /note="LNR 3" FT REPEAT 1827..1871 FT /note="ANK 1" FT REPEAT 1876..1905 FT /note="ANK 2" FT REPEAT 1909..1939 FT /note="ANK 3" FT REPEAT 1943..1972 FT /note="ANK 4" FT REPEAT 1976..2005 FT /note="ANK 5" FT REPEAT 2009..2038 FT /note="ANK 6" FT REGION 1425..1677 FT /note="Negative regulatory region (NRR)" FT REGION 1754..1788 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2091..2168 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2380..2471 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1760..1788 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2123..2138 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2139..2168 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2384..2403 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2419..2447 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 614 FT /note="Essential for O-xylosylation" FT /evidence="ECO:0000250|UniProtKB:O35516" FT MOD_RES 1716 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1778 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 1802 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1804 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1808 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 1842 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O35516" FT MOD_RES 1845 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332" FT MOD_RES 2070 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 2078 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q9QW30" FT MOD_RES 2081 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 2097 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT CARBOHYD 46 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 155 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 613 FT /note="O-linked (Glc...) serine; alternate" FT /evidence="ECO:0000250|UniProtKB:O35516" FT CARBOHYD 613 FT /note="O-linked (Xyl...) serine; alternate" FT /evidence="ECO:0000250|UniProtKB:O35516" FT CARBOHYD 733 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1102 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 1465 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 28..41 FT /evidence="ECO:0000250" FT DISULFID 35..51 FT /evidence="ECO:0000250" FT DISULFID 53..62 FT /evidence="ECO:0000250" FT DISULFID 68..79 FT /evidence="ECO:0000250" FT DISULFID 73..90 FT /evidence="ECO:0000250" FT DISULFID 92..101 FT /evidence="ECO:0000250" FT DISULFID 109..121 FT /evidence="ECO:0000250" FT DISULFID 115..131 FT /evidence="ECO:0000250" FT DISULFID 133..142 FT /evidence="ECO:0000250" FT DISULFID 148..159 FT /evidence="ECO:0000250" FT DISULFID 153..168 FT /evidence="ECO:0000250" FT DISULFID 170..179 FT /evidence="ECO:0000250" FT DISULFID 186..198 FT /evidence="ECO:0000250" FT DISULFID 192..207 FT /evidence="ECO:0000250" FT DISULFID 209..218 FT /evidence="ECO:0000250" FT DISULFID 225..236 FT /evidence="ECO:0000250" FT DISULFID 230..246 FT /evidence="ECO:0000250" FT DISULFID 248..257 FT /evidence="ECO:0000250" FT DISULFID 264..275 FT /evidence="ECO:0000250" FT DISULFID 269..284 FT /evidence="ECO:0000250" FT DISULFID 286..295 FT /evidence="ECO:0000250" FT DISULFID 302..315 FT /evidence="ECO:0000250" FT DISULFID 309..324 FT /evidence="ECO:0000250" FT DISULFID 326..335 FT /evidence="ECO:0000250" FT DISULFID 342..353 FT /evidence="ECO:0000250" FT DISULFID 347..362 FT /evidence="ECO:0000250" FT DISULFID 364..373 FT /evidence="ECO:0000250" FT DISULFID 379..390 FT /evidence="ECO:0000250" FT DISULFID 384..401 FT /evidence="ECO:0000250" FT DISULFID 403..412 FT /evidence="ECO:0000250" FT DISULFID 419..433 FT /evidence="ECO:0000250" FT DISULFID 427..442 FT /evidence="ECO:0000250" FT DISULFID 444..453 FT /evidence="ECO:0000250" FT DISULFID 460..471 FT /evidence="ECO:0000250" FT DISULFID 465..480 FT /evidence="ECO:0000250" FT DISULFID 482..491 FT /evidence="ECO:0000250" FT DISULFID 498..509 FT /evidence="ECO:0000250" FT DISULFID 503..518 FT /evidence="ECO:0000250" FT DISULFID 520..529 FT /evidence="ECO:0000250" FT DISULFID 536..547 FT /evidence="ECO:0000250" FT DISULFID 541..556 FT /evidence="ECO:0000250" FT DISULFID 558..567 FT /evidence="ECO:0000250" FT DISULFID 574..584 FT /evidence="ECO:0000250" FT DISULFID 579..593 FT /evidence="ECO:0000250" FT DISULFID 595..604 FT /evidence="ECO:0000250" FT DISULFID 611..622 FT /evidence="ECO:0000250" FT DISULFID 616..631 FT /evidence="ECO:0000250" FT DISULFID 633..642 FT /evidence="ECO:0000250" FT DISULFID 649..659 FT /evidence="ECO:0000250" FT DISULFID 654..668 FT /evidence="ECO:0000250" FT DISULFID 670..679 FT /evidence="ECO:0000250" FT DISULFID 686..697 FT /evidence="ECO:0000250" FT DISULFID 691..706 FT /evidence="ECO:0000250" FT DISULFID 708..717 FT /evidence="ECO:0000250" FT DISULFID 724..734 FT /evidence="ECO:0000250" FT DISULFID 729..743 FT /evidence="ECO:0000250" FT DISULFID 745..754 FT /evidence="ECO:0000250" FT DISULFID 761..772 FT /evidence="ECO:0000250" FT DISULFID 766..781 FT /evidence="ECO:0000250" FT DISULFID 783..792 FT /evidence="ECO:0000250" FT DISULFID 799..810 FT /evidence="ECO:0000250" FT DISULFID 804..819 FT /evidence="ECO:0000250" FT DISULFID 821..830 FT /evidence="ECO:0000250" FT DISULFID 837..848 FT /evidence="ECO:0000250" FT DISULFID 842..859 FT /evidence="ECO:0000250" FT DISULFID 861..870 FT /evidence="ECO:0000250" FT DISULFID 877..888 FT /evidence="ECO:0000250" FT DISULFID 882..897 FT /evidence="ECO:0000250" FT DISULFID 899..908 FT /evidence="ECO:0000250" FT DISULFID 915..926 FT /evidence="ECO:0000250" FT DISULFID 920..935 FT /evidence="ECO:0000250" FT DISULFID 937..946 FT /evidence="ECO:0000250" FT DISULFID 953..964 FT /evidence="ECO:0000250" FT DISULFID 958..973 FT /evidence="ECO:0000250" FT DISULFID 975..984 FT /evidence="ECO:0000250" FT DISULFID 991..1002 FT /evidence="ECO:0000250" FT DISULFID 996..1011 FT /evidence="ECO:0000250" FT DISULFID 1013..1022 FT /evidence="ECO:0000250" FT DISULFID 1029..1040 FT /evidence="ECO:0000250" FT DISULFID 1034..1049 FT /evidence="ECO:0000250" FT DISULFID 1051..1060 FT /evidence="ECO:0000250" FT DISULFID 1067..1078 FT /evidence="ECO:0000250" FT DISULFID 1072..1087 FT /evidence="ECO:0000250" FT DISULFID 1089..1098 FT /evidence="ECO:0000250" FT DISULFID 1105..1126 FT /evidence="ECO:0000305" FT DISULFID 1120..1135 FT /evidence="ECO:0000250" FT DISULFID 1137..1146 FT /evidence="ECO:0000250" FT DISULFID 1153..1164 FT /evidence="ECO:0000250" FT DISULFID 1158..1173 FT /evidence="ECO:0000250" FT DISULFID 1175..1184 FT /evidence="ECO:0000250" FT DISULFID 1191..1202 FT /evidence="ECO:0000250" FT DISULFID 1196..1211 FT /evidence="ECO:0000250" FT DISULFID 1213..1222 FT /evidence="ECO:0000250" FT DISULFID 1229..1241 FT /evidence="ECO:0000250" FT DISULFID 1235..1250 FT /evidence="ECO:0000250" FT DISULFID 1252..1261 FT /evidence="ECO:0000250" FT DISULFID 1268..1281 FT /evidence="ECO:0000250" FT DISULFID 1273..1290 FT /evidence="ECO:0000250" FT DISULFID 1292..1301 FT /evidence="ECO:0000250" FT DISULFID 1308..1319 FT /evidence="ECO:0000250" FT DISULFID 1313..1331 FT /evidence="ECO:0000250" FT DISULFID 1333..1342 FT /evidence="ECO:0000250" FT DISULFID 1378..1389 FT /evidence="ECO:0000250" FT DISULFID 1383..1400 FT /evidence="ECO:0000250" FT DISULFID 1402..1411 FT /evidence="ECO:0000250" FT DISULFID 1425..1448 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1430..1443 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1439..1455 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1466..1489 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1472..1484 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1480..1496 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1503..1527 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1509..1522 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1518..1534 FT /evidence="ECO:0000269|PubMed:17401372" FT DISULFID 1632..1639 FT /evidence="ECO:0000269|PubMed:17401372" FT VARIANT 444 FT /note="C -> Y (in ALGS2; dbSNP:rs111033632)" FT /evidence="ECO:0000269|PubMed:16773578" FT /id="VAR_029361" FT VARIANT 1667 FT /note="V -> F (in dbSNP:rs17024517)" FT /id="VAR_031463" FT VARIANT 2140..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378985" FT /id="VAR_080195" FT VARIANT 2196..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:23389697" FT /id="VAR_080196" FT VARIANT 2208..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378985, FT ECO:0000269|PubMed:21681853" FT /id="VAR_080197" FT VARIANT 2223..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21681853" FT /id="VAR_080198" FT VARIANT 2285..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378989" FT /id="VAR_080199" FT VARIANT 2299..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21712856" FT /id="VAR_080200" FT VARIANT 2317..2471 FT /note="Missing (in HJCYS; loss of interaction with FBW7; FT decreased ubiquitination)" FT /evidence="ECO:0000269|PubMed:21378989, FT ECO:0000269|PubMed:29149593" FT /id="VAR_080201" FT VARIANT 2325..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378985" FT /id="VAR_080202" FT VARIANT 2360..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21681853" FT /id="VAR_080203" FT VARIANT 2373..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378989" FT /id="VAR_080204" FT VARIANT 2389..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21712856" FT /id="VAR_080205" FT VARIANT 2400..2471 FT /note="Missing (in HJCYS)" FT /evidence="ECO:0000269|PubMed:21378985, FT ECO:0000269|PubMed:21793104, ECO:0000269|PubMed:23389697" FT /id="VAR_080206" FT MUTAGEN 2416 FT /note="T->A: Loss of interaction with FBW7. Results in FT decreased ubiquitination and degradation." FT /evidence="ECO:0000269|PubMed:29149593" FT CONFLICT 21 FT /note="A -> T (in Ref. 2; AAG37073)" FT /evidence="ECO:0000305" FT CONFLICT 210 FT /note="P -> L (in Ref. 2; AAG37073)" FT /evidence="ECO:0000305" FT CONFLICT 1037 FT /note="E -> D (in Ref. 4; AAB19224)" FT /evidence="ECO:0000305" FT CONFLICT 1084..1085 FT /note="ES -> SP (in Ref. 4; AAB19224)" FT /evidence="ECO:0000305" FT CONFLICT 1094 FT /note="A -> V (in Ref. 4; AAB19224)" FT /evidence="ECO:0000305" FT CONFLICT 1139 FT /note="L -> V (in Ref. 4; AAB19224)" FT /evidence="ECO:0000305" FT CONFLICT 1519 FT /note="D -> N (in Ref. 1; AAA36377)" FT /evidence="ECO:0000305" FT CONFLICT 2053 FT /note="R -> H (in Ref. 2; AAG37073)" FT /evidence="ECO:0000305" FT TURN 418..420 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 432..436 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 439..443 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 448..450 FT /evidence="ECO:0007829|PDB:5MWB" FT HELIX 459..462 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 470..474 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 477..481 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 486..488 FT /evidence="ECO:0007829|PDB:5MWB" FT HELIX 497..500 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 508..512 FT /evidence="ECO:0007829|PDB:5MWB" FT STRAND 515..519 FT /evidence="ECO:0007829|PDB:5MWB" FT HELIX 1428..1433 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1436..1438 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1441..1443 FT /evidence="ECO:0007829|PDB:2OO4" FT TURN 1446..1448 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1449..1452 FT /evidence="ECO:0007829|PDB:2OO4" FT TURN 1453..1458 FT /evidence="ECO:0007829|PDB:2OO4" FT TURN 1462..1465 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1472..1474 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1477..1479 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1482..1484 FT /evidence="ECO:0007829|PDB:2OO4" FT TURN 1487..1490 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1491..1494 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1506..1512 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1515..1517 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1520..1522 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1525..1532 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1544..1553 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1555..1560 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1562..1573 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1575..1579 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1589..1595 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1618..1628 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1632..1635 FT /evidence="ECO:0007829|PDB:2OO4" FT HELIX 1643..1656 FT /evidence="ECO:0007829|PDB:2OO4" FT STRAND 1663..1670 FT /evidence="ECO:0007829|PDB:2OO4" SQ SEQUENCE 2471 AA; 265405 MW; 605B1B963C812BE1 CRC64; MPALRPALLW ALLALWLCCA APAHALQCRD GYEPCVNEGM CVTYHNGTGY CKCPEGFLGE YCQHRDPCEK NRCQNGGTCV AQAMLGKATC RCASGFTGED CQYSTSHPCF VSRPCLNGGT CHMLSRDTYE CTCQVGFTGK ECQWTDACLS HPCANGSTCT TVANQFSCKC LTGFTGQKCE TDVNECDIPG HCQHGGTCLN LPGSYQCQCP QGFTGQYCDS LYVPCAPSPC VNGGTCRQTG DFTFECNCLP GFEGSTCERN IDDCPNHRCQ NGGVCVDGVN TYNCRCPPQW TGQFCTEDVD ECLLQPNACQ NGGTCANRNG GYGCVCVNGW SGDDCSENID DCAFASCTPG STCIDRVASF SCMCPEGKAG LLCHLDDACI SNPCHKGALC DTNPLNGQYI CTCPQGYKGA DCTEDVDECA MANSNPCEHA GKCVNTDGAF HCECLKGYAG PRCEMDINEC HSDPCQNDAT CLDKIGGFTC LCMPGFKGVH CELEINECQS NPCVNNGQCV DKVNRFQCLC PPGFTGPVCQ IDIDDCSSTP CLNGAKCIDH PNGYECQCAT GFTGVLCEEN IDNCDPDPCH HGQCQDGIDS YTCICNPGYM GAICSDQIDE CYSSPCLNDG RCIDLVNGYQ CNCQPGTSGV NCEINFDDCA SNPCIHGICM DGINRYSCVC SPGFTGQRCN IDIDECASNP CRKGATCING VNGFRCICPE GPHHPSCYSQ VNECLSNPCI HGNCTGGLSG YKCLCDAGWV GINCEVDKNE CLSNPCQNGG TCDNLVNGYR CTCKKGFKGY NCQVNIDECA SNPCLNQGTC FDDISGYTCH CVLPYTGKNC QTVLAPCSPN PCENAAVCKE SPNFESYTCL CAPGWQGQRC TIDIDECISK PCMNHGLCHN TQGSYMCECP PGFSGMDCEE DIDDCLANPC QNGGSCMDGV NTFSCLCLPG FTGDKCQTDM NECLSEPCKN GGTCSDYVNS YTCKCQAGFD GVHCENNINE CTESSCFNGG TCVDGINSFS CLCPVGFTGS FCLHEINECS SHPCLNEGTC VDGLGTYRCS CPLGYTGKNC QTLVNLCSRS PCKNKGTCVQ KKAESQCLCP SGWAGAYCDV PNVSCDIAAS RRGVLVEHLC QHSGVCINAG NTHYCQCPLG YTGSYCEEQL DECASNPCQH GATCSDFIGG YRCECVPGYQ GVNCEYEVDE CQNQPCQNGG TCIDLVNHFK CSCPPGTRGL LCEENIDDCA RGPHCLNGGQ CMDRIGGYSC RCLPGFAGER CEGDINECLS NPCSSEGSLD CIQLTNDYLC VCRSAFTGRH CETFVDVCPQ MPCLNGGTCA VASNMPDGFI CRCPPGFSGA RCQSSCGQVK CRKGEQCVHT ASGPRCFCPS PRDCESGCAS SPCQHGGSCH PQRQPPYYSC QCAPPFSGSR CELYTAPPST PPATCLSQYC ADKARDGVCD EACNSHACQW DGGDCSLTME NPWANCSSPL PCWDYINNQC DELCNTVECL FDNFECQGNS KTCKYDKYCA DHFKDNHCDQ GCNSEECGWD GLDCAADQPE NLAEGTLVIV VLMPPEQLLQ DARSFLRALG TLLHTNLRIK RDSQGELMVY PYYGEKSAAM KKQRMTRRSL PGEQEQEVAG SKVFLEIDNR QCVQDSDHCF KNTDAAAALL ASHAIQGTLS YPLVSVVSES LTPERTQLLY LLAVAVVIIL FIILLGVIMA KRKRKHGSLW LPEGFTLRRD ASNHKRREPV GQDAVGLKNL SVQVSEANLI GTGTSEHWVD DEGPQPKKVK AEDEALLSEE DDPIDRRPWT QQHLEAADIR RTPSLALTPP QAEQEVDVLD VNVRGPDGCT PLMLASLRGG SSDLSDEDED AEDSSANIIT DLVYQGASLQ AQTDRTGEMA LHLAARYSRA DAAKRLLDAG ADANAQDNMG RCPLHAAVAA DAQGVFQILI RNRVTDLDAR MNDGTTPLIL AARLAVEGMV AELINCQADV NAVDDHGKSA LHWAAAVNNV EATLLLLKNG ANRDMQDNKE ETPLFLAARE GSYEAAKILL DHFANRDITD HMDRLPRDVA RDRMHHDIVR LLDEYNVTPS PPGTVLTSAL SPVICGPNRS FLSLKHTPMG KKSRRPSAKS TMPTSLPNLA KEAKDAKGSR RKKSLSEKVQ LSESSVTLSP VDSLESPHTY VSDTTSSPMI TSPGILQASP NPMLATAAPP APVHAQHALS FSNLHEMQPL AHGASTVLPS VSQLLSHHHI VSPGSGSAGS LSRLHPVPVP ADWMNRMEVN ETQYNEMFGM VLAPAEGTHP GIAPQSRPPE GKHITTPREP LPPIVTFQLI PKGSIAQPAG APQPQSTCPP AVAGPLPTMY QIPEMARLPS VAFPTAMMPQ QDGQVAQTIL PAYHPFPASV GKYPTPPSQH SYASSNAAER TPSHSGHLQG EHPYLTPSPE SPDQWSSSSP HSASDWSDVT TSPTPGGAGG GQRGPGTHMS EPPHNNMQVY A //