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Protein

E3 ubiquitin-protein ligase DTX3L

Gene

DTX3L

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses (PubMed:12670957, PubMed:19818714, PubMed:26479788, PubMed:23230272). Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4 (PubMed:28525742). In response to DNA damage, mediates monoubiquitination of 'Lys-91' of histone H4 (H4K91ub1) (PubMed:19818714). The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 'Lys-20' methylation (H4K20me) (PubMed:19818714). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). By monoubiquitinating histone H2B HIST1H2BH/H2BJ and thereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication (PubMed:26479788). Independently of its catalytic activity, promotes the sorting of chemokine receptor CXCR4 from early endosome to lysosome following CXCL12 stimulation by reducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitination of endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:24790097). In addition, required for the recruitment of HGS and STAM to early endosomes (PubMed:24790097). In association with PARP9, plays a role in antiviral responses by mediating 'Lys-48'-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting their proteosomal-mediated degradation (PubMed:26479788).6 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.5 Publications

Enzyme regulationi

Binding to PARP9 enhances DTX3L catalytic activity.1 Publication

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.5 Publications
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri561 – 600RING-typePROSITE-ProRule annotationAdd BLAST40

GO - Molecular functioni

  • enzyme activator activity Source: UniProtKB
  • enzyme binding Source: UniProtKB
  • enzyme inhibitor activity Source: UniProtKB
  • histone binding Source: UniProtKB
  • metal ion binding Source: UniProtKB-KW
  • RNA binding Source: InterPro
  • STAT family protein binding Source: UniProtKB
  • ubiquitin-like protein ligase binding Source: UniProtKB
  • ubiquitin-protein transferase activity Source: UniProtKB

GO - Biological processi

  • cellular response to DNA damage stimulus Source: UniProtKB
  • defense response to virus Source: UniProtKB-KW
  • double-strand break repair Source: UniProtKB
  • endosome to lysosome transport Source: UniProtKB
  • histone H2A ubiquitination Source: UniProtKB
  • histone H2B ubiquitination Source: UniProtKB
  • histone monoubiquitination Source: UniProtKB
  • innate immune response Source: UniProtKB-KW
  • negative regulation of ubiquitin-protein transferase activity Source: UniProtKB
  • positive regulation of chromatin binding Source: UniProtKB
  • positive regulation of defense response to virus by host Source: UniProtKB
  • positive regulation of double-strand break repair via nonhomologous end joining Source: UniProtKB
  • positive regulation of NAD+ ADP-ribosyltransferase activity Source: UniProtKB
  • positive regulation of protein binding Source: UniProtKB
  • positive regulation of protein localization to early endosome Source: UniProtKB
  • positive regulation of protein localization to nucleus Source: UniProtKB
  • positive regulation of receptor catabolic process Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • protein autoubiquitination Source: UniProtKB
  • protein K48-linked ubiquitination Source: UniProtKB
  • protein polyubiquitination Source: Reactome
  • protein transport Source: UniProtKB-KW
  • protein ubiquitination involved in ubiquitin-dependent protein catabolic process Source: UniProtKB

Keywordsi

Molecular functionChromatin regulator, Transferase
Biological processAntiviral defense, DNA damage, DNA repair, Immunity, Innate immunity, Protein transport, Transport, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase DTX3L (EC:2.3.2.275 Publications)
Alternative name(s):
B-lymphoma- and BAL-associated protein
Protein deltex-3-like
RING-type E3 ubiquitin transferase DTX3LCurated
Rhysin-2
Short name:
Rhysin2
Gene namesi
Name:DTX3L
Synonyms:BBAP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000163840.9.
HGNCiHGNC:30323. DTX3L.
MIMi613143. gene.

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

Cytoplasm, Endosome, Lysosome, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi561 – 564CVIC → SVIS: Loss of catalytic activity. Loss of histone H2B ubiquitination. No effect on STAT1 phosphorylation and on the interaction with PARP9 and STAT1. 1 Publication4
Mutagenesisi561C → A: Loss of catalytic activity but does not affect its capacity to inhibit ITCH catalytic activity; when associated with A-596 and A-599. 1 Publication1
Mutagenesisi596C → A: Loss of catalytic activity but does not affect its capacity to inhibit ITCH catalytic activity; when associated with A-561 and A-599. 1 Publication1
Mutagenesisi599C → A: Loss of catalytic activity but does not affect its capacity to inhibit ITCH catalytic activity; when associated with A-561 and A-596. 1 Publication1

Organism-specific databases

DisGeNETi151636.
OpenTargetsiENSG00000163840.
PharmGKBiPA134864792.

Polymorphism and mutation databases

BioMutaiDTX3L.
DMDMi37077418.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedCombined sources
ChainiPRO_00002190872 – 740E3 ubiquitin-protein ligase DTX3LAdd BLAST739

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineCombined sources1
Modified residuei9PhosphoserineCombined sources1
Modified residuei202PhosphoserineCombined sources1
Modified residuei221PhosphoserineCombined sources1
Modified residuei532PhosphoserineCombined sources1
Modified residuei539PhosphoserineCombined sources1

Post-translational modificationi

Autoubiquitinated.1 Publication

Keywords - PTMi

Acetylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8TDB6.
MaxQBiQ8TDB6.
PaxDbiQ8TDB6.
PeptideAtlasiQ8TDB6.
PRIDEiQ8TDB6.

PTM databases

iPTMnetiQ8TDB6.
PhosphoSitePlusiQ8TDB6.

Expressioni

Inductioni

Induced by IFNG (PubMed:16809771, PubMed:26479788). Induced by IFNB1 (PubMed:26479788).2 Publications

Gene expression databases

BgeeiENSG00000163840.
CleanExiHS_DTX3L.
GenevisibleiQ8TDB6. HS.

Organism-specific databases

HPAiHPA010570.

Interactioni

Subunit structurei

Homodimer and heterodimer (PubMed:12670957, PubMed:28525742). Can heterodimerize with DTX1, enhancing its ubiquitin ligase activity in vitro (PubMed:12670957). Interacts (via N-terminus) with ADP ribosyltransferase PARP9/BAL1 (via PARP catalytic domain) forming a stable complex; the interaction is required to activate PARP9 but is dispensable for DTX3L catalytic activity (PubMed:12670957, PubMed:23230272, PubMed:26479788, PubMed:28525742). Forms a complex with STAT1 and PARP9 independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Found in a complex with PARP9, STAT1 and HIST1H2BH (PubMed:26479788). Found in a complex with E3 ligase ITCH and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts (via C-terminus) with ITCH; the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity; the interaction is direct (PubMed:24790097). Interacts with HGS and STAM; the interaction brings together HGS and STAM and promotes their recruitment to early endosomes (PubMed:24790097).5 Publications
(Microbial infection) Interacts with encephalomyocarditis virus (EMCV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination.1 Publication
(Microbial infection) Interacts with human rhinovirus (HRV) C3 protease; the interaction results in C3 protease 'Lys-48'-linked ubiquitination.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
SPG21Q9NZD85EBI-2340392,EBI-742688

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • histone binding Source: UniProtKB
  • STAT family protein binding Source: UniProtKB
  • ubiquitin-like protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi127392. 38 interactors.
IntActiQ8TDB6. 17 interactors.
STRINGi9606.ENSP00000296161.

Structurei

Secondary structure

1740
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi612 – 622Combined sources11
Beta strandi630 – 639Combined sources10
Beta strandi648 – 650Combined sources3
Beta strandi658 – 667Combined sources10
Helixi668 – 682Combined sources15
Beta strandi686 – 692Combined sources7
Turni693 – 696Combined sources4
Beta strandi697 – 703Combined sources7
Beta strandi712 – 714Combined sources3
Helixi716 – 718Combined sources3
Helixi726 – 736Combined sources11

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
3PG6X-ray1.70A/B/C/D601-740[»]
ProteinModelPortaliQ8TDB6.
SMRiQ8TDB6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the Deltex family.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri561 – 600RING-typePROSITE-ProRule annotationAdd BLAST40

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiENOG410IEH5. Eukaryota.
ENOG4111QEI. LUCA.
GeneTreeiENSGT00440000035370.
HOGENOMiHOG000112292.
HOVERGENiHBG051417.
InParanoidiQ8TDB6.
KOiK06058.
OMAiCNLFSKE.
OrthoDBiEOG091G06M5.
PhylomeDBiQ8TDB6.
TreeFamiTF325526.

Family and domain databases

Gene3Di3.30.1370.10. 1 hit.
3.30.40.10. 1 hit.
InterProiView protein in InterPro
IPR036612. KH_dom_type_1_sf.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
SMARTiView protein in SMART
SM00184. RING. 1 hit.
PROSITEiView protein in PROSITE
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8TDB6-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MASHLRPPSP LLVRVYKSGP RVRRKLESYF QSSKSSGGGE CTVSTQEHEA
60 70 80 90 100
PGTFRVEFSE RAAKERVLKK GEHQILVDEK PVPIFLVPTE NSIKKNTRPQ
110 120 130 140 150
ISSLTQSQAE TPSGDMHQHE GHIPNAVDSC LQKIFLTVTA DLNCNLFSKE
160 170 180 190 200
QRAYITTLCP SIRKMEGHDG IEKVCGDFQD IERIHQFLSE QFLESEQKQQ
210 220 230 240 250
FSPSMTERKP LSQQERDSCI SPSEPETKAE QKSNYFEVPL PYFEYFKYIC
260 270 280 290 300
PDKINSIEKR FGVNIEIQES SPNMVCLDFT SSRSGDLEAA RESFASEFQK
310 320 330 340 350
NTEPLKQECV SLADSKQANK FKQELNHQFT KLLIKEKGGE LTLLGTQDDI
360 370 380 390 400
SAAKQKISEA FVKIPVKLFA ANYMMNVIEV DSAHYKLLET ELLQEISEIE
410 420 430 440 450
KRYDICSKVS EKGQKTCILF ESKDRQVDLS VHAYASFIDA FQHASCQLMR
460 470 480 490 500
EVLLLKSLGK ERKHLHQTKF ADDFRKRHPN VHFVLNQESM TLTGLPNHLA
510 520 530 540 550
KAKQYVLKGG GMSSLAGKKL KEGHETPMDI DSDDSKAASP PLKGSVSSEA
560 570 580 590 600
SELDKKEKGI CVICMDTISN KKVLPKCKHE FCAPCINKAM SYKPICPTCQ
610 620 630 640 650
TSYGIQKGNQ PEGSMVFTVS RDSLPGYESF GTIVITYSMK AGIQTEEHPN
660 670 680 690 700
PGKRYPGIQR TAYLPDNKEG RKVLKLLYRA FDQKLIFTVG YSRVLGVSDV
710 720 730 740
ITWNDIHHKT SRFGGPEMYG YPDPSYLKRV KEELKAKGIE
Length:740
Mass (Da):83,554
Last modified:June 1, 2002 - v1
Checksum:iC413BB744CEE6223
GO
Isoform 2 (identifier: Q8TDB6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     134-645: Missing.

Note: No experimental confirmation available.
Show »
Length:228
Mass (Da):25,792
Checksum:i4553DE0866AFEC99
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti701I → T in AAV98362 (Ref. 4) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_036098209K → N in a breast cancer sample; somatic mutation. 1 Publication1
Natural variantiVAR_048895425R → K2 PublicationsCorresponds to variant dbSNP:rs2332285Ensembl.1
Natural variantiVAR_048896668K → M. Corresponds to variant dbSNP:rs9868175Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_038522134 – 645Missing in isoform 2. 1 PublicationAdd BLAST512

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY225123 mRNA. Translation: AAP57517.1.
AF484416 mRNA. Translation: AAL90859.1.
AK125086 mRNA. Translation: BAG54138.1.
AY780792 mRNA. Translation: AAV98362.1.
CH471052 Genomic DNA. Translation: EAW79476.1.
BC042191 mRNA. Translation: AAH42191.1.
BC060509 mRNA. Translation: AAH60509.1.
CCDSiCCDS3015.1. [Q8TDB6-1]
RefSeqiNP_612144.1. NM_138287.3. [Q8TDB6-1]
UniGeneiHs.518201.

Genome annotation databases

EnsembliENST00000296161; ENSP00000296161; ENSG00000163840. [Q8TDB6-1]
ENST00000383661; ENSP00000373157; ENSG00000163840. [Q8TDB6-2]
GeneIDi151636.
KEGGihsa:151636.
UCSCiuc003efk.4. human. [Q8TDB6-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiDTX3L_HUMAN
AccessioniPrimary (citable) accession number: Q8TDB6
Secondary accession number(s): B3KWH6, Q53ZZ3, Q5MJP7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 26, 2003
Last sequence update: June 1, 2002
Last modified: December 20, 2017
This is version 142 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, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families