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Database: UniProt
Entry: Q04721
LinkDB: Q04721
Original site: Q04721 
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   10-APR-2019, entry version 221.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; 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.,
RA   Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA   Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA   McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA   Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA   Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA   Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA   Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA   Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA   Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA   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.,
RA   Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA   Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA   Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA   Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA   Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA   Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA   Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA   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.,
RA   Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA   Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA   Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA   Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA   Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA   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
RT   a 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
RT   the 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.,
RA   Banks A., 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
RT   transcriptional 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
RT   coactivators 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.,
RA   Mann M.;
RT   "Global, in vivo, and site-specific phosphorylation dynamics in
RT   signaling 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
RT   factor inhibiting hypoxia-inducible factor.";
RL   J. Biol. Chem. 282:24027-24038(2007).
RN   [12]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-1716; THR-1802;
RP   SER-1804; THR-1808; SER-1845; SER-2070; SER-2081 AND THR-2097, AND
RP   IDENTIFICATION BY 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   [13]
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.,
RA   Peet D.J., Lendahl U., Poellinger L.;
RT   "Interaction with factor inhibiting HIF-1 defines an additional mode
RT   of cross-coupling between the Notch and hypoxia signaling pathways.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:3368-3373(2008).
RN   [14]
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   [15]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1778, AND IDENTIFICATION
RP   BY 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.,
RA   Mann M.;
RT   "Quantitative phosphoproteomics reveals widespread full
RT   phosphorylation site occupancy during mitosis.";
RL   Sci. Signal. 3:RA3-RA3(2010).
RN   [16]
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.,
RA   Marcadier J., Fryns J.P., Boycott K.M., Ste-Marie L.G.,
RA   McKiernan F.E., Marik I., 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   [17]
RP   FUNCTION, INVOLVEMENT IN HJCYS, AND VARIANTS HJCYS 2285-GLN--ALA-2471
RP   DEL; 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.,
RA   Jacquemont S., Martin-Coignard D., Thauvin-Robinet C., Le Merrer M.,
RA   Mandel J.L., David A., Faivre L., Cormier-Daire V., Redon R.,
RA   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   [18]
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
RP   AND 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.,
RA   Elmslie F.V., Mansour S., Holder S.E., Brain C.E., Burton B.K.,
RA   Kim K.H., Pauli R.M., Aftimos S., Stewart H., Kim C.A.,
RA   Holder-Espinasse M., Robertson S.P., Drake W.M., Trembath R.C.;
RT   "Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe
RT   and progressive bone loss.";
RL   Nat. Genet. 43:303-305(2011).
RN   [19]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1778, AND IDENTIFICATION
RP   BY 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   [20]
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
RT   via suppression of NOTCH2 signalling.";
RL   Nat. Commun. 6:7122-7122(2015).
RN   [21]
RP   FUNCTION, PHOSPHORYLATION BY GSK3, UBIQUITINATION, INTERACTION WITH
RP   CUL1; SKP1; RBX1 AND FBW7, MUTAGENESIS OF THR-2416, AND
RP   CHARACTERIZATION OF 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.,
RA   Inuzuka H.;
RT   "NOTCH2 Hajdu-Cheney mutations escape SCFFBW7-dependent proteolysis to
RT   promote osteoporosis.";
RL   Mol. Cell 68:645-658(2017).
RN   [22]
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.,
RA   Rosenkrantz J.L., Lorig-Roach R., Field A.R., Haeussler M., Russo L.,
RA   Bhaduri A., Nowakowski T.J., Pollen A.A., Dougherty M.L., Nuttle X.,
RA   Addor M.C., Zwolinski S., Katzman S., Kriegstein A., Eichler E.E.,
RA   Salama S.R., 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   [23]
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
RT   breast cancer growth.";
RL   J. Mol. Cell Biol. 10:195-204(2018).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1426-1677, AND DISULFIDE
RP   BONDS.
RX   PubMed=17401372; DOI=10.1038/nsmb1227;
RA   Gordon W.R., Vardar-Ulu D., Histen G., Sanchez-Irizarry C.,
RA   Aster J.C., Blacklow S.C.;
RT   "Structural basis for autoinhibition of Notch.";
RL   Nat. Struct. Mol. Biol. 14:295-300(2007).
RN   [25]
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
RT   the notch signaling pathway.";
RL   Am. J. Hum. Genet. 79:169-173(2006).
RN   [26]
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   [27]
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.,
RA   Simpson M.A., Irving M.D., Robertson S.P.;
RT   "Serpentine fibula polycystic kidney syndrome is part of the
RT   phenotypic spectrum of Hajdu-Cheney syndrome.";
RL   Eur. J. Hum. Genet. 20:122-124(2012).
RN   [28]
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
CC       Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate
CC       cell-fate determination. Upon ligand activation through the
CC       released notch intracellular domain (NICD) it forms a
CC       transcriptional activator complex with RBPJ/RBPSUH and activates
CC       genes of the enhancer of split locus (PubMed:21378985,
CC       PubMed:21378989). Affects the implementation of differentiation,
CC       proliferation and apoptotic programs (By similarity). Involved in
CC       bone remodeling and homeostasis. In collaboration with RELA/p65
CC       enhances NFATc1 promoter activity and positively regulates RANKL-
CC       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-
CC       terminal fragment N(EC) which are probably linked by disulfide
CC       bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which
CC       act as transcriptional coactivators for NOTCH2. Interacts with
CC       RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via
CC       ANK repeats) with TCIM, the interaction inhibits the nuclear
CC       translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with
CC       CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-
CC       protein ligase complex components (PubMed:29149593). Interacts
CC       with MINAR1; this interaction increases MINAR1 stability and
CC       function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA,
CC       NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling
CC       pathway in a non-cell-autonomous manner (PubMed:29856954).
CC       {ECO:0000250, ECO:0000269|PubMed:11101851,
CC       ECO:0000269|PubMed:12370315, ECO:0000269|PubMed:17573339,
CC       ECO:0000269|PubMed:25985737, ECO:0000269|PubMed:29149593,
CC       ECO:0000269|PubMed:29329397, ECO:0000269|PubMed:29856954}.
CC   -!- SUBCELLULAR LOCATION: Notch 2 extracellular truncation: Cell
CC       membrane {ECO:0000269|PubMed:29329397,
CC       ECO:0000269|PubMed:9244302}; Single-pass type I membrane protein
CC       {ECO:0000269|PubMed:9244302}.
CC   -!- SUBCELLULAR LOCATION: Notch 2 intracellular domain: Nucleus
CC       {ECO:0000269|PubMed:25985737}. Cytoplasm
CC       {ECO:0000269|PubMed:25985737}. Note=Following proteolytical
CC       processing NICD is translocated to the nucleus. Retained at the
CC       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
CC       which is proteolytically cleaved by a furin-like convertase in the
CC       trans-Golgi network before it reaches the plasma membrane to yield
CC       an active, ligand-accessible form (By similarity). Cleavage
CC       results in a C-terminal fragment N(TM) and a N-terminal fragment
CC       N(EC) (By similarity). Following ligand binding, it is cleaved by
CC       TNF-alpha converting enzyme (TACE) to yield a membrane-associated
CC       intermediate fragment called notch extracellular truncation (NEXT)
CC       (By similarity). This fragment is then cleaved by presenilin
CC       dependent gamma-secretase to release a notch-derived peptide
CC       containing the intracellular domain (NICD) from the membrane (By
CC       similarity). {ECO:0000250|UniProtKB:O35516,
CC       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
CC       necessary for NOTCH2 recognition by FBXW7, ubiquitination and
CC       degradation via the ubiquitin proteasome pathway.
CC       {ECO:0000269|PubMed:29149593}.
CC   -!- DISEASE: Alagille syndrome 2 (ALGS2) [MIM:610205]: A form of
CC       Alagille syndrome, an autosomal dominant multisystem disorder. It
CC       is clinically defined by hepatic bile duct paucity and cholestasis
CC       in association with cardiac, skeletal, and ophthalmologic
CC       manifestations. There are characteristic facial features and less
CC       frequent clinical involvement of the renal and vascular systems.
CC       {ECO:0000269|PubMed:16773578}. Note=The disease is caused by
CC       mutations affecting the gene represented in this entry.
CC   -!- DISEASE: Hajdu-Cheney syndrome (HJCYS) [MIM:102500]: A rare,
CC       autosomal dominant skeletal disorder characterized by the
CC       association of facial anomalies, acro-osteolysis, general
CC       osteoporosis, insufficient ossification of the skull, and
CC       periodontal disease (premature loss of permanent teeth). Other
CC       features include cleft palate, congenital heart defects,
CC       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}.
CC       Note=The disease is caused by mutations affecting the gene
CC       represented in this entry. NOTCH2 nonsense and frameshift
CC       mutations associated with Hajdu-Cheney syndrome cluster to the
CC       last coding exon of the gene. Mutant mRNA products escape
CC       nonsense-mediated decay and the resulting truncated NOTCH2
CC       proteins act in a gain-of-function manner (PubMed:21378989). The
CC       pathological mechanism at cellular level involves disruption of a
CC       high affinity degron recognized by FBXW7 at the C-terminus, loss
CC       of interaction with FBXW7, reduced ubiquitination and degradation,
CC       and increased NOTCH2 levels. Bone marrow cells derived from HJCYS
CC       patients have an enhanced capacity of osteoclastogenesis due to
CC       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
CC       and Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/NOTCH2ID41556ch1p12.html";
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   UniGene; Hs.487360; -.
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   ProteinModelPortal; Q04721; -.
DR   SMR; Q04721; -.
DR   BioGrid; 110915; 58.
DR   CORUM; Q04721; -.
DR   ELM; Q04721; -.
DR   IntAct; Q04721; 36.
DR   MINT; Q04721; -.
DR   STRING; 9606.ENSP00000256646; -.
DR   BindingDB; Q04721; -.
DR   ChEMBL; CHEMBL3407320; -.
DR   GuidetoPHARMACOLOGY; 2859; -.
DR   GlyConnect; 1553; -.
DR   iPTMnet; Q04721; -.
DR   PhosphoSitePlus; Q04721; -.
DR   BioMuta; NOTCH2; -.
DR   DMDM; 143811429; -.
DR   EPD; Q04721; -.
DR   jPOST; Q04721; -.
DR   MaxQB; Q04721; -.
DR   PaxDb; Q04721; -.
DR   PeptideAtlas; Q04721; -.
DR   PRIDE; Q04721; -.
DR   ProteomicsDB; 58265; -.
DR   Ensembl; ENST00000256646; ENSP00000256646; ENSG00000134250.
DR   GeneID; 4853; -.
DR   KEGG; hsa:4853; -.
DR   UCSC; uc001eik.4; human.
DR   CTD; 4853; -.
DR   DisGeNET; 4853; -.
DR   EuPathDB; HostDB:ENSG00000134250.17; -.
DR   GeneCards; NOTCH2; -.
DR   GeneReviews; NOTCH2; -.
DR   HGNC; HGNC:7882; NOTCH2.
DR   HPA; HPA048743; -.
DR   MalaCards; NOTCH2; -.
DR   MIM; 102500; phenotype.
DR   MIM; 600275; gene.
DR   MIM; 610205; phenotype.
DR   neXtProt; NX_Q04721; -.
DR   OpenTargets; ENSG00000134250; -.
DR   Orphanet; 955; Acroosteolysis dominant type.
DR   Orphanet; 261629; Alagille syndrome due to a NOTCH2 point mutation.
DR   PharmGKB; PA31684; -.
DR   eggNOG; ENOG410IR7G; Eukaryota.
DR   eggNOG; COG0666; LUCA.
DR   GeneTree; ENSGT00940000155030; -.
DR   HOGENOM; HOG000234369; -.
DR   HOVERGEN; HBG052650; -.
DR   InParanoid; Q04721; -.
DR   KO; K20994; -.
DR   OrthoDB; 1337265at2759; -.
DR   PhylomeDB; Q04721; -.
DR   TreeFam; TF351641; -.
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   ChiTaRS; NOTCH2; human.
DR   EvolutionaryTrace; Q04721; -.
DR   GeneWiki; Notch-2; -.
DR   GenomeRNAi; 4853; -.
DR   PRO; PR:Q04721; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   Bgee; ENSG00000134250; Expressed in 238 organ(s), highest expression level in testis.
DR   ExpressionAtlas; Q04721; baseline and differential.
DR   Genevisible; Q04721; HS.
DR   GO; GO:0009986; C:cell surface; IDA:UniProtKB.
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:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
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: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:0046849; P:bone remodeling; IMP:UniProtKB.
DR   GO; GO:0007050; P:cell cycle arrest; IDA:UniProtKB.
DR   GO; GO:0001709; P:cell fate determination; TAS:UniProtKB.
DR   GO; GO:0030097; P:hemopoiesis; TAS:UniProtKB.
DR   GO; GO:0002315; P:marginal zone B cell differentiation; ISS:UniProtKB.
DR   GO; GO:0007275; P:multicellular organism development; NAS:UniProtKB.
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:0045967; P:negative regulation of growth rate; IDA:UniProtKB.
DR   GO; GO:0007399; P:nervous system development; NAS:UniProtKB.
DR   GO; GO:0061314; P:Notch signaling involved in heart development; IC:BHF-UCL.
DR   GO; GO:0007219; P:Notch signaling pathway; IDA:UniProtKB.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR   GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IDA:UniProtKB.
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:0006355; P:regulation of transcription, DNA-templated; IEA:InterPro.
DR   GO; GO:0019827; P:stem cell population maintenance; TAS:UniProtKB.
DR   GO; GO:0006367; P:transcription initiation from RNA polymerase II promoter; TAS:Reactome.
DR   CDD; cd00204; ANK; 2.
DR   Gene3D; 1.25.40.20; -; 1.
DR   InterPro; IPR002110; Ankyrin_rpt.
DR   InterPro; IPR020683; Ankyrin_rpt-contain_dom.
DR   InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR   InterPro; IPR024600; DUF3454_notch.
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; IPR000800; Notch_dom.
DR   InterPro; IPR010660; Notch_NOD_dom.
DR   InterPro; IPR011656; Notch_NODP_dom.
DR   Pfam; PF12796; Ank_2; 1.
DR   Pfam; PF11936; DUF3454; 1.
DR   Pfam; PF00008; EGF; 24.
DR   Pfam; PF07645; EGF_CA; 4.
DR   Pfam; PF12661; hEGF; 3.
DR   Pfam; PF06816; NOD; 1.
DR   Pfam; PF07684; NODP; 1.
DR   Pfam; PF00066; Notch; 3.
DR   PIRSF; PIRSF002279; Notch; 1.
DR   PRINTS; PR01452; LNOTCHREPEAT.
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; SSF48403; 1.
DR   SUPFAM; SSF57184; SSF57184; 6.
DR   SUPFAM; SSF90193; SSF90193; 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.
PE   1: Evidence at protein level;
KW   3D-structure; Activator; ANK repeat; Cell membrane; Complete proteome;
KW   Cytoplasm; Developmental protein; Differentiation; Disease mutation;
KW   Disulfide bond; EGF-like domain; Glycoprotein; Membrane;
KW   Notch signaling pathway; Nucleus; Phosphoprotein; Receptor;
KW   Reference proteome; Repeat; Signal; Transcription;
KW   Transcription regulation; Transmembrane; Transmembrane helix;
KW   Ubl conjugation.
FT   SIGNAL        1     25       {ECO:0000255}.
FT   CHAIN        26   2471       Neurogenic locus notch homolog protein 2.
FT                                /FTId=PRO_0000007683.
FT   CHAIN      1666   2471       Notch 2 extracellular truncation.
FT                                {ECO:0000250|UniProtKB:Q01705}.
FT                                /FTId=PRO_0000007684.
FT   CHAIN      1697   2471       Notch 2 intracellular domain.
FT                                {ECO:0000250|UniProtKB:O35516}.
FT                                /FTId=PRO_0000007685.
FT   TOPO_DOM     26   1677       Extracellular. {ECO:0000255}.
FT   TRANSMEM   1678   1698       Helical. {ECO:0000255}.
FT   TOPO_DOM   1699   2471       Cytoplasmic. {ECO:0000255}.
FT   DOMAIN       26     63       EGF-like 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN       64    102       EGF-like 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      105    143       EGF-like 3. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      144    180       EGF-like 4. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      182    219       EGF-like 5; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      221    258       EGF-like 6. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      260    296       EGF-like 7; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      298    336       EGF-like 8; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      338    374       EGF-like 9; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      375    413       EGF-like 10. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      415    454       EGF-like 11; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      456    492       EGF-like 12; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      494    530       EGF-like 13; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      532    568       EGF-like 14; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      570    605       EGF-like 15; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      607    643       EGF-like 16; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      645    680       EGF-like 17; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      682    718       EGF-like 18; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      720    755       EGF-like 19. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      757    793       EGF-like 20; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      795    831       EGF-like 21; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      833    871       EGF-like 22. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN      873    909       EGF-like 23; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      911    947       EGF-like 24; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      949    985       EGF-like 25; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN      987   1023       EGF-like 26; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1025   1061       EGF-like 27; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1063   1099       EGF-like 28. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1101   1147       EGF-like 29. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1149   1185       EGF-like 30; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1187   1223       EGF-like 31; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1225   1262       EGF-like 32; calcium-binding.
FT                                {ECO:0000255|PROSITE-ProRule:PRU00076}.
FT   DOMAIN     1264   1302       EGF-like 33. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1304   1343       EGF-like 34. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   DOMAIN     1374   1412       EGF-like 35. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00076}.
FT   REPEAT     1425   1465       LNR 1.
FT   REPEAT     1466   1502       LNR 2.
FT   REPEAT     1503   1544       LNR 3.
FT   REPEAT     1827   1871       ANK 1.
FT   REPEAT     1876   1905       ANK 2.
FT   REPEAT     1909   1939       ANK 3.
FT   REPEAT     1943   1972       ANK 4.
FT   REPEAT     1976   2005       ANK 5.
FT   REPEAT     2009   2038       ANK 6.
FT   REGION     1425   1677       Negative regulatory region (NRR).
FT   COMPBIAS   1645   1648       Poly-Ala.
FT   COMPBIAS   1994   1997       Poly-Leu.
FT   COMPBIAS   2426   2429       Poly-Ser.
FT   SITE        614    614       Essential for O-xylosylation.
FT                                {ECO:0000250|UniProtKB:O35516}.
FT   MOD_RES    1716   1716       Phosphothreonine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    1778   1778       Phosphoserine.
FT                                {ECO:0000244|PubMed:19690332,
FT                                ECO:0000244|PubMed:20068231,
FT                                ECO:0000244|PubMed:23186163}.
FT   MOD_RES    1802   1802       Phosphothreonine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    1804   1804       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    1808   1808       Phosphothreonine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    1842   1842       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:O35516}.
FT   MOD_RES    1845   1845       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648,
FT                                ECO:0000244|PubMed:19690332}.
FT   MOD_RES    2070   2070       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    2078   2078       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:Q9QW30}.
FT   MOD_RES    2081   2081       Phosphoserine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   MOD_RES    2097   2097       Phosphothreonine.
FT                                {ECO:0000244|PubMed:18669648}.
FT   CARBOHYD     46     46       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    155    155       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD    613    613       O-linked (Glc...) serine; alternate.
FT                                {ECO:0000250|UniProtKB:O35516}.
FT   CARBOHYD    613    613       O-linked (Xyl...) serine; alternate.
FT                                {ECO:0000250|UniProtKB:O35516}.
FT   CARBOHYD    733    733       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1102   1102       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   CARBOHYD   1465   1465       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID     28     41       {ECO:0000250}.
FT   DISULFID     35     51       {ECO:0000250}.
FT   DISULFID     53     62       {ECO:0000250}.
FT   DISULFID     68     79       {ECO:0000250}.
FT   DISULFID     73     90       {ECO:0000250}.
FT   DISULFID     92    101       {ECO:0000250}.
FT   DISULFID    109    121       {ECO:0000250}.
FT   DISULFID    115    131       {ECO:0000250}.
FT   DISULFID    133    142       {ECO:0000250}.
FT   DISULFID    148    159       {ECO:0000250}.
FT   DISULFID    153    168       {ECO:0000250}.
FT   DISULFID    170    179       {ECO:0000250}.
FT   DISULFID    186    198       {ECO:0000250}.
FT   DISULFID    192    207       {ECO:0000250}.
FT   DISULFID    209    218       {ECO:0000250}.
FT   DISULFID    225    236       {ECO:0000250}.
FT   DISULFID    230    246       {ECO:0000250}.
FT   DISULFID    248    257       {ECO:0000250}.
FT   DISULFID    264    275       {ECO:0000250}.
FT   DISULFID    269    284       {ECO:0000250}.
FT   DISULFID    286    295       {ECO:0000250}.
FT   DISULFID    302    315       {ECO:0000250}.
FT   DISULFID    309    324       {ECO:0000250}.
FT   DISULFID    326    335       {ECO:0000250}.
FT   DISULFID    342    353       {ECO:0000250}.
FT   DISULFID    347    362       {ECO:0000250}.
FT   DISULFID    364    373       {ECO:0000250}.
FT   DISULFID    379    390       {ECO:0000250}.
FT   DISULFID    384    401       {ECO:0000250}.
FT   DISULFID    403    412       {ECO:0000250}.
FT   DISULFID    419    433       {ECO:0000250}.
FT   DISULFID    427    442       {ECO:0000250}.
FT   DISULFID    444    453       {ECO:0000250}.
FT   DISULFID    460    471       {ECO:0000250}.
FT   DISULFID    465    480       {ECO:0000250}.
FT   DISULFID    482    491       {ECO:0000250}.
FT   DISULFID    498    509       {ECO:0000250}.
FT   DISULFID    503    518       {ECO:0000250}.
FT   DISULFID    520    529       {ECO:0000250}.
FT   DISULFID    536    547       {ECO:0000250}.
FT   DISULFID    541    556       {ECO:0000250}.
FT   DISULFID    558    567       {ECO:0000250}.
FT   DISULFID    574    584       {ECO:0000250}.
FT   DISULFID    579    593       {ECO:0000250}.
FT   DISULFID    595    604       {ECO:0000250}.
FT   DISULFID    611    622       {ECO:0000250}.
FT   DISULFID    616    631       {ECO:0000250}.
FT   DISULFID    633    642       {ECO:0000250}.
FT   DISULFID    649    659       {ECO:0000250}.
FT   DISULFID    654    668       {ECO:0000250}.
FT   DISULFID    670    679       {ECO:0000250}.
FT   DISULFID    686    697       {ECO:0000250}.
FT   DISULFID    691    706       {ECO:0000250}.
FT   DISULFID    708    717       {ECO:0000250}.
FT   DISULFID    724    734       {ECO:0000250}.
FT   DISULFID    729    743       {ECO:0000250}.
FT   DISULFID    745    754       {ECO:0000250}.
FT   DISULFID    761    772       {ECO:0000250}.
FT   DISULFID    766    781       {ECO:0000250}.
FT   DISULFID    783    792       {ECO:0000250}.
FT   DISULFID    799    810       {ECO:0000250}.
FT   DISULFID    804    819       {ECO:0000250}.
FT   DISULFID    821    830       {ECO:0000250}.
FT   DISULFID    837    848       {ECO:0000250}.
FT   DISULFID    842    859       {ECO:0000250}.
FT   DISULFID    861    870       {ECO:0000250}.
FT   DISULFID    877    888       {ECO:0000250}.
FT   DISULFID    882    897       {ECO:0000250}.
FT   DISULFID    899    908       {ECO:0000250}.
FT   DISULFID    915    926       {ECO:0000250}.
FT   DISULFID    920    935       {ECO:0000250}.
FT   DISULFID    937    946       {ECO:0000250}.
FT   DISULFID    953    964       {ECO:0000250}.
FT   DISULFID    958    973       {ECO:0000250}.
FT   DISULFID    975    984       {ECO:0000250}.
FT   DISULFID    991   1002       {ECO:0000250}.
FT   DISULFID    996   1011       {ECO:0000250}.
FT   DISULFID   1013   1022       {ECO:0000250}.
FT   DISULFID   1029   1040       {ECO:0000250}.
FT   DISULFID   1034   1049       {ECO:0000250}.
FT   DISULFID   1051   1060       {ECO:0000250}.
FT   DISULFID   1067   1078       {ECO:0000250}.
FT   DISULFID   1072   1087       {ECO:0000250}.
FT   DISULFID   1089   1098       {ECO:0000250}.
FT   DISULFID   1105   1126       {ECO:0000250}.
FT   DISULFID   1120   1135       {ECO:0000250}.
FT   DISULFID   1137   1146       {ECO:0000250}.
FT   DISULFID   1153   1164       {ECO:0000250}.
FT   DISULFID   1158   1173       {ECO:0000250}.
FT   DISULFID   1175   1184       {ECO:0000250}.
FT   DISULFID   1191   1202       {ECO:0000250}.
FT   DISULFID   1196   1211       {ECO:0000250}.
FT   DISULFID   1213   1222       {ECO:0000250}.
FT   DISULFID   1229   1241       {ECO:0000250}.
FT   DISULFID   1235   1250       {ECO:0000250}.
FT   DISULFID   1252   1261       {ECO:0000250}.
FT   DISULFID   1268   1281       {ECO:0000250}.
FT   DISULFID   1273   1290       {ECO:0000250}.
FT   DISULFID   1292   1301       {ECO:0000250}.
FT   DISULFID   1308   1319       {ECO:0000250}.
FT   DISULFID   1313   1331       {ECO:0000250}.
FT   DISULFID   1333   1342       {ECO:0000250}.
FT   DISULFID   1378   1389       {ECO:0000250}.
FT   DISULFID   1383   1400       {ECO:0000250}.
FT   DISULFID   1402   1411       {ECO:0000250}.
FT   DISULFID   1425   1448       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1430   1443       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1439   1455       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1466   1489       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1472   1484       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1480   1496       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1503   1527       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1509   1522       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1518   1534       {ECO:0000269|PubMed:17401372}.
FT   DISULFID   1632   1639       {ECO:0000269|PubMed:17401372}.
FT   VARIANT     444    444       C -> Y (in ALGS2; dbSNP:rs111033632).
FT                                {ECO:0000269|PubMed:16773578}.
FT                                /FTId=VAR_029361.
FT   VARIANT    1667   1667       V -> F (in dbSNP:rs17024517).
FT                                /FTId=VAR_031463.
FT   VARIANT    2140   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378985}.
FT                                /FTId=VAR_080195.
FT   VARIANT    2196   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:23389697}.
FT                                /FTId=VAR_080196.
FT   VARIANT    2208   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378985,
FT                                ECO:0000269|PubMed:21681853}.
FT                                /FTId=VAR_080197.
FT   VARIANT    2223   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21681853}.
FT                                /FTId=VAR_080198.
FT   VARIANT    2285   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378989}.
FT                                /FTId=VAR_080199.
FT   VARIANT    2299   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21712856}.
FT                                /FTId=VAR_080200.
FT   VARIANT    2317   2471       Missing (in HJCYS; loss of interaction
FT                                with FBW7; decreased ubiquitination).
FT                                {ECO:0000269|PubMed:21378989,
FT                                ECO:0000269|PubMed:29149593}.
FT                                /FTId=VAR_080201.
FT   VARIANT    2325   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378985}.
FT                                /FTId=VAR_080202.
FT   VARIANT    2360   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21681853}.
FT                                /FTId=VAR_080203.
FT   VARIANT    2373   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378989}.
FT                                /FTId=VAR_080204.
FT   VARIANT    2389   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21712856}.
FT                                /FTId=VAR_080205.
FT   VARIANT    2400   2471       Missing (in HJCYS).
FT                                {ECO:0000269|PubMed:21378985,
FT                                ECO:0000269|PubMed:21793104,
FT                                ECO:0000269|PubMed:23389697}.
FT                                /FTId=VAR_080206.
FT   MUTAGEN    2416   2416       T->A: Loss of interaction with FBW7.
FT                                Results in decreased ubiquitination and
FT                                degradation.
FT                                {ECO:0000269|PubMed:29149593}.
FT   CONFLICT     21     21       A -> T (in Ref. 2; AAG37073).
FT                                {ECO:0000305}.
FT   CONFLICT    210    210       P -> L (in Ref. 2; AAG37073).
FT                                {ECO:0000305}.
FT   CONFLICT   1037   1037       E -> D (in Ref. 4; AAB19224).
FT                                {ECO:0000305}.
FT   CONFLICT   1084   1085       ES -> SP (in Ref. 4; AAB19224).
FT                                {ECO:0000305}.
FT   CONFLICT   1094   1094       A -> V (in Ref. 4; AAB19224).
FT                                {ECO:0000305}.
FT   CONFLICT   1139   1139       L -> V (in Ref. 4; AAB19224).
FT                                {ECO:0000305}.
FT   CONFLICT   1519   1519       D -> N (in Ref. 1; AAA36377).
FT                                {ECO:0000305}.
FT   CONFLICT   2053   2053       R -> H (in Ref. 2; AAG37073).
FT                                {ECO:0000305}.
FT   TURN        418    420       {ECO:0000244|PDB:5MWB}.
FT   STRAND      426    428       {ECO:0000244|PDB:5MWB}.
FT   STRAND      432    436       {ECO:0000244|PDB:5MWB}.
FT   STRAND      439    443       {ECO:0000244|PDB:5MWB}.
FT   STRAND      448    450       {ECO:0000244|PDB:5MWB}.
FT   HELIX       459    462       {ECO:0000244|PDB:5MWB}.
FT   STRAND      470    474       {ECO:0000244|PDB:5MWB}.
FT   STRAND      477    481       {ECO:0000244|PDB:5MWB}.
FT   STRAND      486    488       {ECO:0000244|PDB:5MWB}.
FT   HELIX       497    500       {ECO:0000244|PDB:5MWB}.
FT   STRAND      508    512       {ECO:0000244|PDB:5MWB}.
FT   STRAND      515    519       {ECO:0000244|PDB:5MWB}.
FT   HELIX      1428   1433       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1436   1438       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1441   1443       {ECO:0000244|PDB:2OO4}.
FT   TURN       1446   1448       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1449   1452       {ECO:0000244|PDB:2OO4}.
FT   TURN       1453   1458       {ECO:0000244|PDB:2OO4}.
FT   TURN       1462   1465       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1472   1474       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1477   1479       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1482   1484       {ECO:0000244|PDB:2OO4}.
FT   TURN       1487   1490       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1491   1494       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1506   1512       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1515   1517       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1520   1522       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1525   1532       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1544   1553       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1555   1560       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1562   1573       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1575   1579       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1589   1595       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1618   1628       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1632   1635       {ECO:0000244|PDB:2OO4}.
FT   HELIX      1643   1656       {ECO:0000244|PDB:2OO4}.
FT   STRAND     1663   1670       {ECO:0000244|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
//
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