NOTC2_HUMAN
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 03-AUG-2022, entry version 241.
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 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 [26]
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 [27]
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 [28]
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 [29]
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). {ECO:0000250, ECO:0000269|PubMed:11101851,
CC ECO:0000269|PubMed:12370315, ECO:0000269|PubMed:17573339,
CC ECO:0000269|PubMed:18469519, ECO:0000269|PubMed:25985737,
CC ECO:0000269|PubMed:29149593, ECO:0000269|PubMed:29329397,
CC ECO:0000269|PubMed:29856954}.
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="http://atlasgeneticsoncology.org/Genes/NOTCH2ID41556ch1p12.html";
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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; 445.
DR CORUM; Q04721; -.
DR ELM; Q04721; -.
DR IntAct; Q04721; 55.
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 GlyGen; Q04721; 11 sites, 2 N-linked glycans (1 site), 2 O-linked glycans (5 sites).
DR iPTMnet; Q04721; -.
DR PhosphoSitePlus; Q04721; -.
DR BioMuta; NOTCH2; -.
DR DMDM; 143811429; -.
DR EPD; Q04721; -.
DR jPOST; Q04721; -.
DR MassIVE; Q04721; -.
DR MaxQB; Q04721; -.
DR PaxDb; Q04721; -.
DR PeptideAtlas; Q04721; -.
DR PRIDE; Q04721; -.
DR ProteomicsDB; 58265; -.
DR ABCD; Q04721; 25 sequenced antibodies.
DR Antibodypedia; 20208; 658 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 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; PGYEGNH; -.
DR OrthoDB; 7525at2759; -.
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 1075 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 203 other tissues.
DR ExpressionAtlas; Q04721; baseline and differential.
DR Genevisible; Q04721; HS.
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: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: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: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:0061314; P:Notch signaling involved in heart development; IC:BHF-UCL.
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: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:0072014; P:proximal tubule development; IEA:Ensembl.
DR GO; GO:0003184; P:pulmonary valve morphogenesis; IMP:BHF-UCL.
DR GO; GO:2000249; P:regulation of actin cytoskeleton reorganization; IDA:UniProtKB.
DR GO; GO:2001204; P:regulation of osteoclast development; IMP:UniProtKB.
DR GO; GO:0042060; P:wound healing; IEA:Ensembl.
DR Gene3D; 1.25.40.20; -; 1.
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 Pfam; PF12796; Ank_2; 1.
DR Pfam; PF13857; Ank_5; 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; 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
