NOTCH4

Protein identityUniProt · HPA

UniProt accession

Q99466

Gene

NOTCH4

Ensembl

ENSG00000204301

Chromosome

6

Canonical length

2003 aa

Protein class

Human disease related genes, Predicted membrane proteins

OverviewNCBI Gene

This gene encodes a member of the NOTCH family of proteins. Members of this Type I transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple different domain types. Notch signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor may play a role in vascular, renal and hepatic development. Mutations in this gene may be associated with schizophrenia. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

Canonical amino-acid sequenceUniProt

2003 residues, UniProt reviewed canonical sequence.

>Q99466|NOTCH4
     1  MQPPSLLLLL LLLLLLCVSV VRPRGLLCGS FPEPCANGGT CLSLSLGQGT CQCAPGFLGE
    61  TCQFPDPCQN AQLCQNGGSC QALLPAPLGL PSSPSPLTPS FLCTCLPGFT GERCQAKLED
   121  PCPPSFCSKR GRCHIQASGR PQCSCMPGWT GEQCQLRDFC SANPCVNGGV CLATYPQIQC
   181  HCPPGFEGHA CERDVNECFQ DPGPCPKGTS CHNTLGSFQC LCPVGQEGPR CELRAGPCPP
   241  RGCSNGGTCQ LMPEKDSTFH LCLCPPGFIG PDCEVNPDNC VSHQCQNGGT CQDGLDTYTC
   301  LCPETWTGWD CSEDVDECET QGPPHCRNGG TCQNSAGSFH CVCVSGWGGT SCEENLDDCI
   361  AATCAPGSTC IDRVGSFSCL CPPGRTGLLC HLEDMCLSQP CHGDAQCSTN PLTGSTLCLC
   421  QPGYSGPTCH QDLDECLMAQ QGPSPCEHGG SCLNTPGSFN CLCPPGYTGS RCEADHNECL
   481  SQPCHPGSTC LDLLATFHCL CPPGLEGQLC EVETNECASA PCLNHADCHD LLNGFQCICL
   541  PGFSGTRCEE DIDECRSSPC ANGGQCQDQP GAFHCKCLPG FEGPRCQTEV DECLSDPCPV
   601  GASCLDLPGA FFCLCPSGFT GQLCEVPLCA PNLCQPKQIC KDQKDKANCL CPDGSPGCAP
   661  PEDNCTCHHG HCQRSSCVCD VGWTGPECEA ELGGCISAPC AHGGTCYPQP SGYNCTCPTG
   721  YTGPTCSEEM TACHSGPCLN GGSCNPSPGG YYCTCPPSHT GPQCQTSTDY CVSAPCFNGG
   781  TCVNRPGTFS CLCAMGFQGP RCEGKLRPSC ADSPCRNRAT CQDSPQGPRC LCPTGYTGGS
   841  CQTLMDLCAQ KPCPRNSHCL QTGPSFHCLC LQGWTGPLCN LPLSSCQKAA LSQGIDVSSL
   901  CHNGGLCVDS GPSYFCHCPP GFQGSLCQDH VNPCESRPCQ NGATCMAQPS GYLCQCAPGY
   961  DGQNCSKELD ACQSQPCHNH GTCTPKPGGF HCACPPGFVG LRCEGDVDEC LDQPCHPTGT
  1021  AACHSLANAF YCQCLPGHTG QWCEVEIDPC HSQPCFHGGT CEATAGSPLG FICHCPKGFE
  1081  GPTCSHRAPS CGFHHCHHGG LCLPSPKPGF PPRCACLSGY GGPDCLTPPA PKGCGPPSPC
  1141  LYNGSCSETT GLGGPGFRCS CPHSSPGPRC QKPGAKGCEG RSGDGACDAG CSGPGGNWDG
  1201  GDCSLGVPDP WKGCPSHSRC WLLFRDGQCH PQCDSEECLF DGYDCETPPA CTPAYDQYCH
  1261  DHFHNGHCEK GCNTAECGWD GGDCRPEDGD PEWGPSLALL VVLSPPALDQ QLFALARVLS
  1321  LTLRVGLWVR KDRDGRDMVY PYPGARAEEK LGGTRDPTYQ ERAAPQTQPL GKETDSLSAG
  1381  FVVVMGVDLS RCGPDHPASR CPWDPGLLLR FLAAMAAVGA LEPLLPGPLL AVHPHAGTAP
  1441  PANQLPWPVL CSPVAGVILL ALGALLVLQL IRRRRREHGA LWLPPGFTRR PRTQSAPHRR
  1501  RPPLGEDSIG LKALKPKAEV DEDGVVMCSG PEEGEEVGQA EETGPPSTCQ LWSLSGGCGA
  1561  LPQAAMLTPP QESEMEAPDL DTRGPDGVTP LMSAVCCGEV QSGTFQGAWL GCPEPWEPLL
  1621  DGGACPQAHT VGTGETPLHL AARFSRPTAA RRLLEAGANP NQPDRAGRTP LHAAVAADAR
  1681  EVCQLLLRSR QTAVDARTED GTTPLMLAAR LAVEDLVEEL IAAQADVGAR DKWGKTALHW
  1741  AAAVNNARAA RSLLQAGADK DAQDNREQTP LFLAAREGAV EVAQLLLGLG AARELRDQAG
  1801  LAPADVAHQR NHWDLLTLLE GAGPPEARHK ATPGREAGPF PRARTVSVSV PPHGGGALPR
  1861  CRTLSAGAGP RGGGACLQAR TWSVDLAARG GGAYSHCRSL SGVGAGGGPT PRGRRFSAGM
  1921  RGPRPNPAIM RGRYGVAAGR GGRVSTDDWP CDWVALGACG SASNIPIPPP CLTPSPERGS
  1981  PQLDCGPPAL QEMPINQGGE GKK

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against NOTCH4 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

1

Mean surface accessibility (rSASA)

0.41

Highest tissue expression

22 nTPM

Expression across tissuesHPA

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.74

gnomAD pLI

0

gnomAD missense Z

2.14

DepMap mean gene effect

-0.08

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• branching involved in blood vessel morphogenesis
• cell differentiation
• cell fate determination
• endothelial cell morphogenesis
• epithelial to mesenchymal transition
• hemopoiesis
• luteolysis
• mammary gland development
• morphogenesis of a branching structure
• negative regulation of cell adhesion molecule production
• negative regulation of cell differentiation
• negative regulation of cell-cell adhesion mediated by cadherin
• negative regulation of endothelial cell differentiation
• negative regulation of transcription by RNA polymerase II
• positive regulation of DNA-templated transcription
• positive regulation of smooth muscle cell differentiation
• positive regulation of transcription by RNA polymerase II
• positive regulation of transcription of Notch receptor target
• vasculature development

Molecular functions

• calcium ion binding
• Notch binding
• signaling receptor activity
• transcription coactivator activity

Cellular components

• cell surface
• cytosol
• endoplasmic reticulum membrane
• extracellular region
• Golgi membrane
• nucleoplasm
• nucleus
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• EGF-type aspartate/asparagine hydroxylation site
• EGF-like domain
• Notch domain
• EGF-like calcium-binding domain
• Ankyrin repeat
• Notch
• Growth factor receptor cysteine-rich domain superfamily
• Notch, NOD domain
• Notch, NODP domain
• EGF-like, conserved site
• EGF-like calcium-binding, conserved site
• Notch-like domain superfamily
• Ankyrin repeat-containing domain superfamily
• NOTCH1, EGF-like calcium-binding domain
• Notch and Slit guidance protein
• EGF-like domain
• LNR domain
• NOTCH protein
• Calcium-binding EGF domain
• NOTCH protein
• Human growth factor-like EGF
• Ankyrin repeats (3 copies)
• Neurogenic locus Notch 4

KeywordsUniProt

• Activator
• ANK repeat
• Cell membrane
• Developmental protein
• Differentiation
• Disulfide bond
• EGF-like domain
• Glycoprotein
• Host-virus interaction
• Membrane
• Notch signaling pathway
• Nucleus
• Phosphoprotein
• Receptor
• Repeat
• Signal
• Transcription
• Transcription regulation
• Transmembrane
• Transmembrane helix
• Triplet repeat expansion

InteractionsUniProt · HPA

Protein binding partners of NOTCH4 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• MAML1
• MAML2
• DLL4