Reviewed, UniProtKB/Swiss-Prot Q04721 (NOTC2_HUMAN)

Names and origin

Protein names

Recommended name:
    Neurogenic locus notch homolog protein 2
      Short name=Notch 2
      Short name=hN2
Cleaved into the following 2 chains:
    1- Recommended name:
            Notch 2 extracellular truncation
    2- Recommended name:
            Notch 2 intracellular domain

Gene names

Name:

NOTCH2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	2471 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBP-J kappa and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs By similarity.
Subunit structure	Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds By similarity. Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Notch 2 intracellular domain: Nucleus. Note= Following proteolytical processing NICD is translocated to the nucleus.
Tissue specificity	Expressed in the brain, heart, kidney, lung, skeletal muscle and liver.
Post-translational modification	Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane By similarity. Phosphorylated By similarity.
Involvement in disease	Defects in NOTCH2 are the cause of Alagille syndrome type 2 (ALGS2) [MIM:610205]. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.
Sequence similarities	Belongs to the NOTCH family. Contains 6 ANK repeats. Contains 35 EGF-like domains. Contains 3 LNR (Lin/Notch) repeats.

Ontologies

Keywords
Biological process	Differentiation Notch signaling pathway Transcription Transcription regulation
Cellular component	Cell membrane Membrane Nucleus
Disease	Disease mutation
Domain	ANK repeat EGF-like domain Repeat Signal Transmembrane
Molecular function	Activator Developmental protein Receptor
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	Notch signaling pathway Inferred from electronic annotation. Source: InterPro anti-apoptosis Traceable author statement. Source: UniProtKB cell cycle arrest Inferred from direct assay. Source: UniProtKB cell fate determination Ref.6 Traceable author statement. Source: UniProtKB cell growth Inferred from direct assay. Source: UniProtKB hemopoiesis Ref.5 Traceable author statement. Source: UniProtKB induction of apoptosis Traceable author statement. Source: UniProtKB negative regulation of cell proliferation Inferred from direct assay. Source: UniProtKB nervous system development Non-traceable author statement. Source: UniProtKB organ morphogenesis Inferred from expression pattern. Source: UniProtKB positive regulation of Ras protein signal transduction Inferred from direct assay. Source: UniProtKB regulation of transcription, DNA-dependent Ref.6 Traceable author statement. Source: UniProtKB stem cell maintenance Traceable author statement. Source: UniProtKB
Cellular component	cell surface Ref.6 Inferred from direct assay. Source: UniProtKB integral to plasma membrane Ref.6 Inferred from direct assay. Source: UniProtKB nucleus Ref.5 Inferred from direct assay. Source: UniProtKB
Molecular function	calcium ion binding Inferred from electronic annotation. Source: InterPro ligand-regulated transcription factor activity Ref.6 Traceable author statement. Source: UniProtKB protein heterodimerization activity Ref.6 Non-traceable author statement. Source: UniProtKB receptor activity Ref.6 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 25	25	Potential
	Chain	26 – 2471	2446	Neurogenic locus notch homolog protein 2		PRO_0000007683
	Chain	1666 – 2471	806	Notch 2 extracellular truncation By similarity		PRO_0000007684
	Chain	1697 – 2471	775	Notch 2 intracellular domain By similarity		PRO_0000007685
Regions
	Topological domain	26 – 1677	1652	Extracellular Potential
	Transmembrane	1678 – 1698	21	Potential
	Topological domain	1699 – 2471	773	Cytoplasmic Potential
	Domain	26 – 63	38	EGF-like 1
	Domain	64 – 102	39	EGF-like 2
	Domain	105 – 143	39	EGF-like 3
	Domain	144 – 180	37	EGF-like 4
	Domain	182 – 219	38	EGF-like 5; calcium-binding Potential
	Domain	221 – 258	38	EGF-like 6
	Domain	260 – 296	37	EGF-like 7; calcium-binding Potential
	Domain	298 – 336	39	EGF-like 8; calcium-binding Potential
	Domain	338 – 374	37	EGF-like 9; calcium-binding Potential
	Domain	375 – 413	39	EGF-like 10
	Domain	415 – 454	40	EGF-like 11; calcium-binding Potential
	Domain	456 – 492	37	EGF-like 12; calcium-binding Potential
	Domain	494 – 530	37	EGF-like 13; calcium-binding Potential
	Domain	532 – 568	37	EGF-like 14; calcium-binding Potential
	Domain	570 – 605	36	EGF-like 15; calcium-binding Potential
	Domain	607 – 643	37	EGF-like 16; calcium-binding Potential
	Domain	645 – 680	36	EGF-like 17; calcium-binding Potential
	Domain	682 – 718	37	EGF-like 18; calcium-binding Potential
	Domain	720 – 755	36	EGF-like 19
	Domain	757 – 793	37	EGF-like 20; calcium-binding Potential
	Domain	795 – 831	37	EGF-like 21; calcium-binding Potential
	Domain	833 – 871	39	EGF-like 22
	Domain	873 – 909	37	EGF-like 23; calcium-binding Potential
	Domain	911 – 947	37	EGF-like 24; calcium-binding Potential
	Domain	949 – 985	37	EGF-like 25; calcium-binding Potential
	Domain	987 – 1023	37	EGF-like 26; calcium-binding Potential
	Domain	1025 – 1061	37	EGF-like 27; calcium-binding Potential
	Domain	1063 – 1099	37	EGF-like 28
	Domain	1101 – 1147	47	EGF-like 29
	Domain	1149 – 1185	37	EGF-like 30; calcium-binding Potential
	Domain	1187 – 1223	37	EGF-like 31; calcium-binding Potential
	Domain	1225 – 1262	38	EGF-like 32; calcium-binding Potential
	Domain	1264 – 1302	39	EGF-like 33
	Domain	1304 – 1343	40	EGF-like 34
	Domain	1374 – 1412	39	EGF-like 35
	Repeat	1425 – 1465	41	LNR 1
	Repeat	1466 – 1502	37	LNR 2
	Repeat	1503 – 1544	42	LNR 3
	Repeat	1827 – 1871	45	ANK 1
	Repeat	1876 – 1905	30	ANK 2
	Repeat	1909 – 1939	31	ANK 3
	Repeat	1943 – 1972	30	ANK 4
	Repeat	1976 – 2005	30	ANK 5
	Repeat	2009 – 2038	30	ANK 6
	Region	1425 – 1677	253	Negative regulatory region (NRR)
	Compositional bias	1645 – 1648	4	Poly-Ala
	Compositional bias	1994 – 1997	4	Poly-Leu
	Compositional bias	2426 – 2429	4	Poly-Ser
Amino acid modifications
	Modified residue	1716	1	Phosphothreonine
	Modified residue	1778	1	Phosphoserine
	Modified residue	1802	1	Phosphothreonine
	Modified residue	1804	1	Phosphoserine
	Modified residue	1808	1	Phosphothreonine
	Modified residue	1841	1	Phosphoserine
	Modified residue	1842	1	Phosphoserine
	Modified residue	1845	1	Phosphoserine
	Modified residue	2070	1	Phosphoserine
	Modified residue	2074	1	Phosphothreonine
	Modified residue	2078	1	Phosphoserine By similarity
	Modified residue	2081	1	Phosphoserine
	Modified residue	2097	1	Phosphothreonine
	Glycosylation	46	1	N-linked (GlcNAc...) Potential
	Glycosylation	155	1	N-linked (GlcNAc...) Potential
	Glycosylation	733	1	N-linked (GlcNAc...) Potential
	Glycosylation	1102	1	N-linked (GlcNAc...) Potential
	Glycosylation	1465	1	N-linked (GlcNAc...) Potential
	Disulfide bond	28 ↔ 41		By similarity
	Disulfide bond	35 ↔ 51		By similarity
	Disulfide bond	53 ↔ 62		By similarity
	Disulfide bond	68 ↔ 79		By similarity
	Disulfide bond	73 ↔ 90		By similarity
	Disulfide bond	92 ↔ 101		By similarity
	Disulfide bond	109 ↔ 121		By similarity
	Disulfide bond	115 ↔ 131		By similarity
	Disulfide bond	133 ↔ 142		By similarity
	Disulfide bond	148 ↔ 159		By similarity
	Disulfide bond	153 ↔ 168		By similarity
	Disulfide bond	170 ↔ 179