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Protein

Delta-like protein 4

Gene

DLL4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).By similarity3 Publications

GO - Molecular functioni

  • calcium ion binding Source: InterPro
  • Notch binding Source: ProtInc

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein
Biological processAngiogenesis, Differentiation, Neurogenesis, Notch signaling pathway, Sensory transduction, Vision

Enzyme and pathway databases

ReactomeiR-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2660826 Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232 Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
SignaLinkiQ9NR61
SIGNORiQ9NR61

Names & Taxonomyi

Protein namesi
Recommended name:
Delta-like protein 4
Alternative name(s):
Drosophila Delta homolog 4
Short name:
Delta4
Gene namesi
Name:DLL4
ORF Names:UNQ1895/PRO4341
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 15

Organism-specific databases

EuPathDBiHostDB:ENSG00000128917.6
HGNCiHGNC:2910 DLL4
MIMi605185 gene
neXtProtiNX_Q9NR61

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini27 – 529ExtracellularSequence analysisAdd BLAST503
Transmembranei530 – 550HelicalSequence analysisAdd BLAST21
Topological domaini551 – 685CytoplasmicSequence analysisAdd BLAST135

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Involvement in diseasei

Adams-Oliver syndrome 6 (AOS6)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of Adams-Oliver syndrome, a disorder characterized by the congenital absence of skin (aplasia cutis congenita) in combination with transverse limb defects. Aplasia cutis congenita can be located anywhere on the body, but in the vast majority of the cases, it is present on the posterior parietal region where it is often associated with an underlying defect of the parietal bones. Limb abnormalities are typically limb truncation defects affecting the distal phalanges or entire digits (true ectrodactyly). Only rarely, metatarsals/metacarpals or more proximal limb structures are also affected. Apart from transverse limb defects, syndactyly, most commonly of second and third toes, can also be observed. The clinical features are highly variable and can also include cardiovascular malformations, brain abnormalities and vascular defects such as cutis marmorata and dilated scalp veins.
See also OMIM:616589
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075858121A → P in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065350EnsemblClinVar.1
Natural variantiVAR_075859186R → C in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065348EnsemblClinVar.1
Natural variantiVAR_075860195F → L in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065351EnsemblClinVar.1
Natural variantiVAR_075861267P → T in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065349EnsemblClinVar.1
Natural variantiVAR_075862390C → R in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065347EnsemblClinVar.1
Natural variantiVAR_075863390C → Y in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065346EnsemblClinVar.1
Natural variantiVAR_075864455C → W in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065345EnsemblClinVar.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi54567
MalaCardsiDLL4
MIMi616589 phenotype
OpenTargetsiENSG00000128917
Orphaneti974 Adams-Oliver syndrome
1114 Aplasia cutis congenita
PharmGKBiPA27366

Chemistry databases

ChEMBLiCHEMBL3712916

Polymorphism and mutation databases

BioMutaiDLL4
DMDMi13431490

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 261 PublicationAdd BLAST26
ChainiPRO_000000751227 – 685Delta-like protein 4Add BLAST659

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi50 ↔ 54By similarity
Disulfide bondi61 ↔ 74By similarity
Glycosylationi108N-linked (GlcNAc...) asparagineBy similarity1
Disulfide bondi175 ↔ 184PROSITE-ProRule annotationBy similarity
Glycosylationi183N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi188 ↔ 200PROSITE-ProRule annotationBy similarity
Glycosylationi205N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi208 ↔ 217PROSITE-ProRule annotationBy similarity
Disulfide bondi222 ↔ 233PROSITE-ProRule annotationBy similarity
Disulfide bondi226 ↔ 239PROSITE-ProRule annotationBy similarity
Disulfide bondi241 ↔ 250PROSITE-ProRule annotationBy similarity
Disulfide bondi253 ↔ 264By similarity
Disulfide bondi259 ↔ 270By similarity
Disulfide bondi272 ↔ 281PROSITE-ProRule annotationBy similarity
Disulfide bondi288 ↔ 300By similarity
Disulfide bondi294 ↔ 310By similarity
Disulfide bondi312 ↔ 321By similarity
Disulfide bondi328 ↔ 339By similarity
Disulfide bondi333 ↔ 348By similarity
Disulfide bondi350 ↔ 359By similarity
Disulfide bondi366 ↔ 377By similarity
Disulfide bondi371 ↔ 388By similarity
Disulfide bondi390 ↔ 399By similarity
Glycosylationi393N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi406 ↔ 417By similarity
Disulfide bondi411 ↔ 426By similarity
Disulfide bondi428 ↔ 437By similarity
Disulfide bondi444 ↔ 455By similarity
Disulfide bondi449 ↔ 464By similarity
Disulfide bondi466 ↔ 475By similarity
Disulfide bondi484 ↔ 495By similarity
Disulfide bondi489 ↔ 506By similarity
Disulfide bondi508 ↔ 517By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiQ9NR61
PaxDbiQ9NR61
PeptideAtlasiQ9NR61
PRIDEiQ9NR61
ProteomicsDBi82285

PTM databases

iPTMnetiQ9NR61
PhosphoSitePlusiQ9NR61

Expressioni

Tissue specificityi

Expressed in vascular endothelium.

Gene expression databases

BgeeiENSG00000128917 Expressed in 170 organ(s), highest expression level in heart left ventricle
CleanExiHS_DLL4
GenevisibleiQ9NR61 HS

Organism-specific databases

HPAiHPA023392

Interactioni

Subunit structurei

Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei110Interaction with Notch1By similarity1
Sitei216Interaction with Notch1By similarity1

Binary interactionsi

WithEntry#Exp.IntActNotes
SYNJ2BPP571053EBI-11700027,EBI-1049004

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ9NR61, 1 interactor
STRINGi9606.ENSP00000249749

Structurei

Secondary structure

1685
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9NR61
SMRiQ9NR61
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini173 – 217DSLPROSITE-ProRule annotationAdd BLAST45
Domaini218 – 251EGF-like 1PROSITE-ProRule annotationAdd BLAST34
Domaini252 – 282EGF-like 2PROSITE-ProRule annotationAdd BLAST31
Domaini284 – 322EGF-like 3PROSITE-ProRule annotationAdd BLAST39
Domaini324 – 360EGF-like 4PROSITE-ProRule annotationAdd BLAST37
Domaini362 – 400EGF-like 5PROSITE-ProRule annotationAdd BLAST39
Domaini402 – 438EGF-like 6PROSITE-ProRule annotationAdd BLAST37
Domaini440 – 476EGF-like 7PROSITE-ProRule annotationAdd BLAST37
Domaini480 – 518EGF-like 8PROSITE-ProRule annotationAdd BLAST39

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni185 – 187Interaction with Notch1By similarity3
Regioni191 – 195Interaction with Notch1By similarity5

Domaini

The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor.

Keywords - Domaini

EGF-like domain, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1217 Eukaryota
ENOG410XP6K LUCA
GeneTreeiENSGT00810000125346
HOGENOMiHOG000267024
HOVERGENiHBG007139
InParanoidiQ9NR61
KOiK06051
OMAiDCARSPC
OrthoDBiEOG091G07YQ
PhylomeDBiQ9NR61
TreeFamiTF351835

Family and domain databases

InterProiView protein in InterPro
IPR001774 DSL
IPR001881 EGF-like_Ca-bd_dom
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR000152 EGF-type_Asp/Asn_hydroxyl_site
IPR009030 Growth_fac_rcpt_cys_sf
IPR011651 Notch_ligand_N
PfamiView protein in Pfam
PF01414 DSL, 1 hit
PF00008 EGF, 5 hits
PF07657 MNNL, 1 hit
SMARTiView protein in SMART
SM00051 DSL, 1 hit
SM00181 EGF, 9 hits
SM00179 EGF_CA, 6 hits
SUPFAMiSSF57184 SSF57184, 1 hit
PROSITEiView protein in PROSITE
PS00010 ASX_HYDROXYL, 1 hit
PS51051 DSL, 1 hit
PS00022 EGF_1, 8 hits
PS01186 EGF_2, 7 hits
PS50026 EGF_3, 8 hits

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9NR61-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MAAASRSASG WALLLLVALW QQRAAGSGVF QLQLQEFINE RGVLASGRPC
60 70 80 90 100
EPGCRTFFRV CLKHFQAVVS PGPCTFGTVS TPVLGTNSFA VRDDSSGGGR
110 120 130 140 150
NPLQLPFNFT WPGTFSLIIE AWHAPGDDLR PEALPPDALI SKIAIQGSLA
160 170 180 190 200
VGQNWLLDEQ TSTLTRLRYS YRVICSDNYY GDNCSRLCKK RNDHFGHYVC
210 220 230 240 250
QPDGNLSCLP GWTGEYCQQP ICLSGCHEQN GYCSKPAECL CRPGWQGRLC
260 270 280 290 300
NECIPHNGCR HGTCSTPWQC TCDEGWGGLF CDQDLNYCTH HSPCKNGATC
310 320 330 340 350
SNSGQRSYTC TCRPGYTGVD CELELSECDS NPCRNGGSCK DQEDGYHCLC
360 370 380 390 400
PPGYYGLHCE HSTLSCADSP CFNGGSCRER NQGANYACEC PPNFTGSNCE
410 420 430 440 450
KKVDRCTSNP CANGGQCLNR GPSRMCRCRP GFTGTYCELH VSDCARNPCA
460 470 480 490 500
HGGTCHDLEN GLMCTCPAGF SGRRCEVRTS IDACASSPCF NRATCYTDLS
510 520 530 540 550
TDTFVCNCPY GFVGSRCEFP VGLPPSFPWV AVSLGVGLAV LLVLLGMVAV
560 570 580 590 600
AVRQLRLRRP DDGSREAMNN LSDFQKDNLI PAAQLKNTNQ KKELEVDCGL
610 620 630 640 650
DKSNCGKQQN HTLDYNLAPG PLGRGTMPGK FPHSDKSLGE KAPLRLHSEK
660 670 680
PECRISAICS PRDSMYQSVC LISEERNECV IATEV
Length:685
Mass (Da):74,605
Last modified:October 1, 2000 - v1
Checksum:i6CF89D3C220ACC89
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_075858121A → P in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065350EnsemblClinVar.1
Natural variantiVAR_075859186R → C in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065348EnsemblClinVar.1
Natural variantiVAR_075860195F → L in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065351EnsemblClinVar.1
Natural variantiVAR_075861267P → T in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065349EnsemblClinVar.1
Natural variantiVAR_075862390C → R in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065347EnsemblClinVar.1
Natural variantiVAR_075863390C → Y in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065346EnsemblClinVar.1
Natural variantiVAR_075864455C → W in AOS6. 1 PublicationCorresponds to variant dbSNP:rs796065345EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF253468 mRNA Translation: AAF76427.1
AB036931 mRNA Translation: BAB16085.1
AB043894 mRNA Translation: BAB18581.1
AY358894 mRNA Translation: AAQ89253.1
BC106950 mRNA Translation: AAI06951.1
AF279305 mRNA Translation: AAF81912.1
CCDSiCCDS45232.1
PIRiJC7570
RefSeqiNP_061947.1, NM_019074.3
UniGeneiHs.511076

Genome annotation databases

EnsembliENST00000249749; ENSP00000249749; ENSG00000128917
GeneIDi54567
KEGGihsa:54567
UCSCiuc001zng.3 human

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF253468 mRNA Translation: AAF76427.1
AB036931 mRNA Translation: BAB16085.1
AB043894 mRNA Translation: BAB18581.1
AY358894 mRNA Translation: AAQ89253.1
BC106950 mRNA Translation: AAI06951.1
AF279305 mRNA Translation: AAF81912.1
CCDSiCCDS45232.1
PIRiJC7570
RefSeqiNP_061947.1, NM_019074.3
UniGeneiHs.511076

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5MVXX-ray2.17A27-325[»]
ProteinModelPortaliQ9NR61
SMRiQ9NR61
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9NR61, 1 interactor
STRINGi9606.ENSP00000249749

Chemistry databases

ChEMBLiCHEMBL3712916

PTM databases

iPTMnetiQ9NR61
PhosphoSitePlusiQ9NR61

Polymorphism and mutation databases

BioMutaiDLL4
DMDMi13431490

Proteomic databases

EPDiQ9NR61
PaxDbiQ9NR61
PeptideAtlasiQ9NR61
PRIDEiQ9NR61
ProteomicsDBi82285

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000249749; ENSP00000249749; ENSG00000128917
GeneIDi54567
KEGGihsa:54567
UCSCiuc001zng.3 human

Organism-specific databases

CTDi54567
DisGeNETi54567
EuPathDBiHostDB:ENSG00000128917.6
GeneCardsiDLL4
HGNCiHGNC:2910 DLL4
HPAiHPA023392
MalaCardsiDLL4
MIMi605185 gene
616589 phenotype
neXtProtiNX_Q9NR61
OpenTargetsiENSG00000128917
Orphaneti974 Adams-Oliver syndrome
1114 Aplasia cutis congenita
PharmGKBiPA27366
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1217 Eukaryota
ENOG410XP6K LUCA
GeneTreeiENSGT00810000125346
HOGENOMiHOG000267024
HOVERGENiHBG007139
InParanoidiQ9NR61
KOiK06051
OMAiDCARSPC
OrthoDBiEOG091G07YQ
PhylomeDBiQ9NR61
TreeFamiTF351835

Enzyme and pathway databases

ReactomeiR-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2660826 Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232 Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
SignaLinkiQ9NR61
SIGNORiQ9NR61

Miscellaneous databases

GeneWikiiDLL4
GenomeRNAii54567
PROiPR:Q9NR61
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000128917 Expressed in 170 organ(s), highest expression level in heart left ventricle
CleanExiHS_DLL4
GenevisibleiQ9NR61 HS

Family and domain databases

InterProiView protein in InterPro
IPR001774 DSL
IPR001881 EGF-like_Ca-bd_dom
IPR013032 EGF-like_CS
IPR000742 EGF-like_dom
IPR000152 EGF-type_Asp/Asn_hydroxyl_site
IPR009030 Growth_fac_rcpt_cys_sf
IPR011651 Notch_ligand_N
PfamiView protein in Pfam
PF01414 DSL, 1 hit
PF00008 EGF, 5 hits
PF07657 MNNL, 1 hit
SMARTiView protein in SMART
SM00051 DSL, 1 hit
SM00181 EGF, 9 hits
SM00179 EGF_CA, 6 hits
SUPFAMiSSF57184 SSF57184, 1 hit
PROSITEiView protein in PROSITE
PS00010 ASX_HYDROXYL, 1 hit
PS51051 DSL, 1 hit
PS00022 EGF_1, 8 hits
PS01186 EGF_2, 7 hits
PS50026 EGF_3, 8 hits
ProtoNetiSearch...

Entry informationi

Entry nameiDLL4_HUMAN
AccessioniPrimary (citable) accession number: Q9NR61
Secondary accession number(s): Q3KP23, Q9NQT9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
Last sequence update: October 1, 2000
Last modified: November 7, 2018
This is version 168 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  2. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  5. Human chromosome 15
    Human chromosome 15: entries, gene names and cross-references to MIM
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Main funding by: National Institutes of Health

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