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Protein

DNA ligase 4

Gene

LIG4

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

Functioni

Efficiently joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends.2 Publications

Catalytic activityi

ATP + (deoxyribonucleotide)(n)-3'-hydroxyl + 5'-phospho-(deoxyribonucleotide)(m) = (deoxyribonucleotide)(n+m) + AMP + diphosphate.PROSITE-ProRule annotation

Cofactori

Mg2+By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei271ATPBy similarity1
Active sitei273N6-AMP-lysine intermediatePROSITE-ProRule annotation1
Binding sitei278ATPBy similarity1
Binding sitei293ATPBy similarity1
Metal bindingi331Magnesium 1Sequence analysis1
Metal bindingi427Magnesium 2Sequence analysis1
Binding sitei432ATPBy similarity1
Binding sitei443ATPBy similarity1
Binding sitei449ATPBy similarity1

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • DNA binding Source: UniProtKB
  • DNA ligase (ATP) activity Source: UniProtKB
  • DNA ligase activity Source: UniProtKB
  • ligase activity Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • protein C-terminus binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionLigase
Biological processCell cycle, Cell division, DNA damage, DNA recombination, DNA repair, DNA replication
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi6.5.1.1 2681
ReactomeiR-HSA-164843 2-LTR circle formation
R-HSA-5693571 Nonhomologous End-Joining (NHEJ)
SignaLinkiP49917
SIGNORiP49917

Names & Taxonomyi

Protein namesi
Recommended name:
DNA ligase 4 (EC:6.5.1.1PROSITE-ProRule annotation)
Alternative name(s):
DNA ligase IV
Polydeoxyribonucleotide synthase [ATP] 4
Gene namesi
Name:LIG4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 13

Organism-specific databases

EuPathDBiHostDB:ENSG00000174405.13
HGNCiHGNC:6601 LIG4
MIMi601837 gene
neXtProtiNX_P49917

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

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Involvement in diseasei

LIG4 syndrome (LIG4S)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionCharacterized by immunodeficiency and developmental and growth delay. Patients display unusual facial features, microcephaly, growth and/or developmental delay, pancytopenia, and various skin abnormalities.
See also OMIM:606593
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_012775469G → E in LIG4S. 1 PublicationCorresponds to variant dbSNP:rs104894420Ensembl.1
Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of severe combined immunodeficiency, a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity.
See also OMIM:602450
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_044123433Missing in RSSCID. 1 Publication1

Keywords - Diseasei

Disease mutation, SCID

Organism-specific databases

DisGeNETi3981
MalaCardsiLIG4
MIMi602450 phenotype
606593 phenotype
OpenTargetsiENSG00000174405
Orphaneti235 Dubowitz syndrome
99812 LIG4 syndrome
39041 Omenn syndrome
PharmGKBiPA30375

Polymorphism and mutation databases

BioMutaiLIG4
DMDMi88911290

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000595761 – 911DNA ligase 4Add BLAST911

Proteomic databases

EPDiP49917
MaxQBiP49917
PaxDbiP49917
PeptideAtlasiP49917
PRIDEiP49917

PTM databases

iPTMnetiP49917
PhosphoSitePlusiP49917

Expressioni

Tissue specificityi

Testis, thymus, prostate and heart.

Gene expression databases

BgeeiENSG00000174405
CleanExiHS_LIG4
ExpressionAtlasiP49917 baseline and differential
GenevisibleiP49917 HS

Organism-specific databases

HPAiHPA001334

Interactioni

Subunit structurei

Interacts with XRCC4. The LIG4-XRCC4 complex has probably a 1:2 stoichiometry. The LIG4-XRCC4 complex associates in a DNA-dependent manner with the DNA-PK complex composed of PRKDC, XRCC6/Ku70 and XRCC5/Ku86 to form the core non-homologous end joining (NHEJ) complex. Additional components of the NHEJ complex include NHEJ1/XLF and PAXX. Interacts with APLF.9 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • protein C-terminus binding Source: UniProtKB

Protein-protein interaction databases

BioGridi110169130 interactors.
CORUMiP49917
DIPiDIP-37958N
IntActiP49917 12 interactors.
MINTiP49917
STRINGi9606.ENSP00000349393

Structurei

Secondary structure

1911
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi10 – 12Combined sources3
Helixi16 – 28Combined sources13
Helixi32 – 53Combined sources22
Turni54 – 56Combined sources3
Helixi65 – 71Combined sources7
Helixi73 – 75Combined sources3
Helixi86 – 96Combined sources11
Helixi104 – 110Combined sources7
Helixi125 – 133Combined sources9
Turni134 – 136Combined sources3
Helixi145 – 160Combined sources16
Helixi164 – 176Combined sources13
Helixi180 – 191Combined sources12
Helixi200 – 207Combined sources8
Helixi211 – 218Combined sources8
Helixi221 – 227Combined sources7
Beta strandi250 – 253Combined sources4
Helixi256 – 258Combined sources3
Helixi259 – 262Combined sources4
Turni263 – 265Combined sources3
Beta strandi268 – 272Combined sources5
Beta strandi276 – 284Combined sources9
Beta strandi287 – 292Combined sources6
Helixi299 – 302Combined sources4
Beta strandi308 – 311Combined sources4
Helixi312 – 315Combined sources4
Helixi316 – 318Combined sources3
Beta strandi324 – 336Combined sources13
Turni337 – 340Combined sources4
Beta strandi341 – 343Combined sources3
Helixi351 – 356Combined sources6
Beta strandi359 – 372Combined sources14
Beta strandi378 – 380Combined sources3
Helixi382 – 392Combined sources11
Turni397 – 399Combined sources3
Beta strandi400 – 402Combined sources3
Beta strandi405 – 408Combined sources4
Helixi411 – 423Combined sources13
Beta strandi429 – 432Combined sources4
Beta strandi443 – 450Combined sources8
Helixi458 – 460Combined sources3
Beta strandi462 – 471Combined sources10
Helixi474 – 478Combined sources5
Beta strandi479 – 488Combined sources10
Beta strandi500 – 507Combined sources8
Helixi513 – 522Combined sources10
Helixi523 – 525Combined sources3
Beta strandi536 – 539Combined sources4
Beta strandi546 – 548Combined sources3
Helixi551 – 553Combined sources3
Beta strandi556 – 560Combined sources5
Beta strandi562 – 566Combined sources5
Beta strandi568 – 570Combined sources3
Beta strandi573 – 578Combined sources6
Beta strandi580 – 584Combined sources5
Helixi590 – 592Combined sources3
Helixi596 – 603Combined sources8
Turni658 – 661Combined sources4
Beta strandi663 – 666Combined sources4
Beta strandi671 – 673Combined sources3
Helixi675 – 684Combined sources10
Beta strandi687 – 692Combined sources6
Beta strandi697 – 701Combined sources5
Helixi707 – 714Combined sources8
Helixi723 – 732Combined sources10
Helixi740 – 742Combined sources3
Beta strandi743 – 745Combined sources3
Helixi748 – 753Combined sources6
Turni754 – 757Combined sources4
Beta strandi764 – 767Combined sources4
Helixi771 – 779Combined sources9
Helixi789 – 802Combined sources14
Helixi809 – 811Combined sources3
Turni812 – 815Combined sources4
Beta strandi817 – 820Combined sources4
Beta strandi823 – 825Combined sources3
Helixi829 – 831Combined sources3
Helixi837 – 847Combined sources11
Beta strandi851 – 855Combined sources5
Beta strandi862 – 865Combined sources4
Helixi872 – 880Combined sources9
Beta strandi887 – 890Combined sources4
Helixi892 – 899Combined sources8
Helixi906 – 908Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1IK9X-ray2.30C748-784[»]
2E2WNMR-A654-759[»]
3II6X-ray2.40X/Y654-911[»]
3VNNX-ray2.90A268-406[»]
3W1BX-ray2.40A1-609[»]
3W1GX-ray2.55A1-609[»]
3W5OX-ray2.84A/B1-609[»]
4HTOX-ray2.81A1-240[»]
4HTPX-ray2.25A/B1-240[»]
ProteinModelPortaliP49917
SMRiP49917
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP49917

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini654 – 743BRCT 1PROSITE-ProRule annotationAdd BLAST90
Domaini808 – 911BRCT 2PROSITE-ProRule annotationAdd BLAST104

Sequence similaritiesi

Belongs to the ATP-dependent DNA ligase family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0966 Eukaryota
COG1793 LUCA
GeneTreeiENSGT00860000133881
HOGENOMiHOG000007831
HOVERGENiHBG005516
InParanoidiP49917
KOiK10777
OMAiHMCPSTK
OrthoDBiEOG091G03K0
PhylomeDBiP49917
TreeFamiTF312980

Family and domain databases

CDDicd00027 BRCT, 2 hits
Gene3Di1.10.3260.101 hit
3.40.50.101902 hits
InterProiView protein in InterPro
IPR001357 BRCT_dom
IPR036420 BRCT_dom_sf
IPR000977 DNA_ligase_ATP-dep
IPR012309 DNA_ligase_ATP-dep_C
IPR012310 DNA_ligase_ATP-dep_cent
IPR016059 DNA_ligase_ATP-dep_CS
IPR012308 DNA_ligase_ATP-dep_N
IPR021536 DNA_ligase_IV_dom
IPR036599 DNA_ligase_N_sf
IPR029710 LIG4
IPR012340 NA-bd_OB-fold
PANTHERiPTHR10459:SF7 PTHR10459:SF7, 2 hits
PfamiView protein in Pfam
PF00533 BRCT, 2 hits
PF04679 DNA_ligase_A_C, 1 hit
PF01068 DNA_ligase_A_M, 1 hit
PF04675 DNA_ligase_A_N, 1 hit
PF11411 DNA_ligase_IV, 1 hit
SMARTiView protein in SMART
SM00292 BRCT, 2 hits
SUPFAMiSSF117018 SSF117018, 1 hit
SSF50249 SSF50249, 1 hit
SSF52113 SSF52113, 2 hits
TIGRFAMsiTIGR00574 dnl1, 1 hit
PROSITEiView protein in PROSITE
PS50172 BRCT, 2 hits
PS00697 DNA_LIGASE_A1, 1 hit
PS00333 DNA_LIGASE_A2, 1 hit
PS50160 DNA_LIGASE_A3, 1 hit

Sequencei

Sequence statusi: Complete.

P49917-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAASQTSQTV ASHVPFADLC STLERIQKSK GRAEKIRHFR EFLDSWRKFH
60 70 80 90 100
DALHKNHKDV TDSFYPAMRL ILPQLERERM AYGIKETMLA KLYIELLNLP
110 120 130 140 150
RDGKDALKLL NYRTPTGTHG DAGDFAMIAY FVLKPRCLQK GSLTIQQVND
160 170 180 190 200
LLDSIASNNS AKRKDLIKKS LLQLITQSSA LEQKWLIRMI IKDLKLGVSQ
210 220 230 240 250
QTIFSVFHND AAELHNVTTD LEKVCRQLHD PSVGLSDISI TLFSAFKPML
260 270 280 290 300
AAIADIEHIE KDMKHQSFYI ETKLDGERMQ MHKDGDVYKY FSRNGYNYTD
310 320 330 340 350
QFGASPTEGS LTPFIHNAFK ADIQICILDG EMMAYNPNTQ TFMQKGTKFD
360 370 380 390 400
IKRMVEDSDL QTCYCVFDVL MVNNKKLGHE TLRKRYEILS SIFTPIPGRI
410 420 430 440 450
EIVQKTQAHT KNEVIDALNE AIDKREEGIM VKQPLSIYKP DKRGEGWLKI
460 470 480 490 500
KPEYVSGLMD ELDILIVGGY WGKGSRGGMM SHFLCAVAEK PPPGEKPSVF
510 520 530 540 550
HTLSRVGSGC TMKELYDLGL KLAKYWKPFH RKAPPSSILC GTEKPEVYIE
560 570 580 590 600
PCNSVIVQIK AAEIVPSDMY KTGCTLRFPR IEKIRDDKEW HECMTLDDLE
610 620 630 640 650
QLRGKASGKL ASKHLYIGGD DEPQEKKRKA APKMKKVIGI IEHLKAPNLT
660 670 680 690 700
NVNKISNIFE DVEFCVMSGT DSQPKPDLEN RIAEFGGYIV QNPGPDTYCV
710 720 730 740 750
IAGSENIRVK NIILSNKHDV VKPAWLLECF KTKSFVPWQP RFMIHMCPST
760 770 780 790 800
KEHFAREYDC YGDSYFIDTD LNQLKEVFSG IKNSNEQTPE EMASLIADLE
810 820 830 840 850
YRYSWDCSPL SMFRRHTVYL DSYAVINDLS TKNEGTRLAI KALELRFHGA
860 870 880 890 900
KVVSCLAEGV SHVIIGEDHS RVADFKAFRR TFKRKFKILK ESWVTDSIDK
910
CELQEENQYL I
Length:911
Mass (Da):103,971
Last modified:February 7, 2006 - v2
Checksum:i2122813E1EFA63B9
GO

Sequence cautioni

The sequence AAL77435 differs from that shown. Reason: Erroneous initiation.Curated
The sequence CAA58467 differs from that shown. Reason: Erroneous initiation.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti246F → S in CAA58467 (PubMed:7760816).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0293523A → V Associated with resistance to multiple myeloma. 1 PublicationCorresponds to variant dbSNP:rs1805389Ensembl.1
Natural variantiVAR_0338849T → I Associated with resistance to multiple myeloma. 1 PublicationCorresponds to variant dbSNP:rs1805388Ensembl.1
Natural variantiVAR_02935362D → H. Corresponds to variant dbSNP:rs3093763Ensembl.1
Natural variantiVAR_018808231P → S1 PublicationCorresponds to variant dbSNP:rs3093765Ensembl.1
Natural variantiVAR_012774278R → H in LIG4S and leukemia; impairs activity. 3 PublicationsCorresponds to variant dbSNP:rs104894421Ensembl.1
Natural variantiVAR_044123433Missing in RSSCID. 1 Publication1
Natural variantiVAR_044124461E → G. Corresponds to variant dbSNP:rs2232640Ensembl.1
Natural variantiVAR_012775469G → E in LIG4S. 1 PublicationCorresponds to variant dbSNP:rs104894420Ensembl.1
Natural variantiVAR_016771539L → F. Corresponds to variant dbSNP:rs3742212Ensembl.1
Natural variantiVAR_016772658I → V. Corresponds to variant dbSNP:rs2232641Ensembl.1
Natural variantiVAR_075826774L → P Found in a patient with microcephalic primordial dwarfism; unknown pathological significance. 1 Publication1
Natural variantiVAR_016773857A → T1 PublicationCorresponds to variant dbSNP:rs2232642Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X83441 mRNA Translation: CAA58467.1 Different initiation.
AF479264 Genomic DNA Translation: AAL77435.1 Different initiation.
AL157762 Genomic DNA No translation available.
BC037491 mRNA Translation: AAH37491.1
CCDSiCCDS9508.1
PIRiI37079
RefSeqiNP_001091738.1, NM_001098268.1
NP_001317524.1, NM_001330595.1
NP_002303.2, NM_002312.3
NP_996820.1, NM_206937.1
XP_005254113.1, XM_005254056.1
XP_005254114.1, XM_005254057.4
XP_005254115.1, XM_005254058.3
XP_006720014.1, XM_006719951.3
XP_006720015.1, XM_006719952.1
XP_011519393.1, XM_011521091.2
XP_011519394.1, XM_011521092.2
XP_016876058.1, XM_017020569.1
XP_016876059.1, XM_017020570.1
XP_016876060.1, XM_017020571.1
XP_016876062.1, XM_017020573.1
UniGeneiHs.166091

Genome annotation databases

EnsembliENST00000356922; ENSP00000349393; ENSG00000174405
ENST00000405925; ENSP00000385955; ENSG00000174405
ENST00000442234; ENSP00000402030; ENSG00000174405
ENST00000611712; ENSP00000484288; ENSG00000174405
GeneIDi3981
KEGGihsa:3981
UCSCiuc001vqn.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiDNLI4_HUMAN
AccessioniPrimary (citable) accession number: P49917
Secondary accession number(s): Q8IY66, Q8TEU5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: February 7, 2006
Last modified: March 28, 2018
This is version 198 of the entry and version 2 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