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Protein

Tyrosyl-DNA phosphodiesterase 2

Gene

TDP2

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

Functioni

DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DNA double-strand breaks/DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Thereby, protects the transcription of many genes involved in neurological development and maintenance from the abortive activity of TOP2. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DSBs due to DNA damage by radiation and free radicals. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Acts as a regulator of ribosome biogenesis following stress. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation.7 Publications
(Microbial infection) Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA.1 Publication

Cofactori

Mg2+3 Publications, Mn2+3 PublicationsNote: Magnesium. Can use other divalent cations as cofactor in vitro, such as manganese.3 Publications

Kineticsi

kcat is 3 sec(-1) with single-stranded 5'-tyrosyl DNA as substrate.
  1. KM=8 µM for single-stranded 5'-tyrosyl DNA1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi120MagnesiumCurated1
    Metal bindingi152MagnesiumBy similarity1
    Metal bindingi262MagnesiumCurated1
    Metal bindingi264MagnesiumBy similarity1
    Metal bindingi350MagnesiumBy similarity1
    Active sitei351Proton acceptorCurated1
    Metal bindingi351MagnesiumCurated1

    GO - Molecular functioni

    GO - Biological processi

    • cell surface receptor signaling pathway Source: ProtInc
    • double-strand break repair Source: UniProtKB
    • neuron development Source: UniProtKB

    Keywordsi

    Molecular functionHydrolase, Nuclease
    Biological processDNA damage, DNA repair
    LigandMagnesium, Metal-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-5693571 Nonhomologous End-Joining (NHEJ)

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Tyrosyl-DNA phosphodiesterase 2 (EC:3.1.4.-)
    Short name:
    Tyr-DNA phosphodiesterase 2
    Short name:
    hTDP2
    Alternative name(s):
    5'-tyrosyl-DNA phosphodiesterase
    Short name:
    5'-Tyr-DNA phosphodiesterase
    ETS1-associated protein 2
    ETS1-associated protein II
    Short name:
    EAPII
    TRAF and TNF receptor-associated protein
    Tyrosyl-RNA phosphodiesterase
    VPg unlinkase
    Gene namesi
    Name:TDP2
    Synonyms:EAP2, TTRAP
    ORF Names:AD-022
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000111802.13
    HGNCiHGNC:17768 TDP2
    MIMi605764 gene
    neXtProtiNX_O95551

    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, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR23 patients manifest epilepsy, intellectual disability, and gait ataxia.
    See also OMIM:616949

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi88T → A: Abolishes function, but retains ability to interact with SMAD3; when associated with A-92. 1 Publication1
    Mutagenesisi92T → A: Abolishes function, but retains ability to interact with SMAD3; when associated with A-88. 1 Publication1
    Mutagenesisi120N → A: Strongly reduced phosphodiesterase activity. 1 Publication1
    Mutagenesisi152E → A: Loss of phosphodiesterase activity. 2 Publications1
    Mutagenesisi262D → A: Loss of phosphodiesterase activity. 2 Publications1
    Mutagenesisi351H → A: Loss of phosphodiesterase activity. 1 Publication1

    Keywords - Diseasei

    Mental retardation, Neurodegeneration, Spinocerebellar ataxia

    Organism-specific databases

    DisGeNETi51567
    MalaCardsiTDP2
    MIMi616949 phenotype
    OpenTargetsiENSG00000111802
    Orphaneti404493 Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency
    PharmGKBiPA165618310

    Chemistry databases

    ChEMBLiCHEMBL2169736

    Polymorphism and mutation databases

    BioMutaiTDP2

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000656781 – 362Tyrosyl-DNA phosphodiesterase 2Add BLAST362

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei1N-acetylmethionineCombined sources1
    Cross-linki23Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Cross-linki82Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
    Modified residuei88Phosphothreonine; by ACVR1B1 Publication1
    Modified residuei92Phosphothreonine; by ACVR1B1 Publication1
    Modified residuei95PhosphoserineCombined sources1

    Post-translational modificationi

    Ubiquitinated by TRAF6.1 Publication

    Keywords - PTMi

    Acetylation, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiO95551
    MaxQBiO95551
    PaxDbiO95551
    PeptideAtlasiO95551
    PRIDEiO95551
    ProteomicsDBi50937
    50938 [O95551-2]
    50939 [O95551-3]

    PTM databases

    iPTMnetiO95551
    PhosphoSitePlusiO95551

    Expressioni

    Tissue specificityi

    Widely expressed (PubMed:10764746). Highly expressed in various brain regions, including the frontal and occipital lobes, the hippocampus, the striatum and the cerebellum (PubMed:24658003).2 Publications

    Gene expression databases

    BgeeiENSG00000111802 Expressed in 236 organ(s), highest expression level in colonic mucosa
    CleanExiHS_TTRAP
    ExpressionAtlasiO95551 baseline and differential
    GenevisibleiO95551 HS

    Organism-specific databases

    HPAiCAB073398
    HPA074011

    Interactioni

    Subunit structurei

    Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4.3 Publications

    Protein-protein interaction databases

    BioGridi119615, 39 interactors
    IntActiO95551, 26 interactors
    MINTiO95551
    STRINGi9606.ENSP00000367440

    Chemistry databases

    BindingDBiO95551

    Structurei

    Secondary structure

    1362
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliO95551
    SMRiO95551
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the CCR4/nocturin family.Curated

    Phylogenomic databases

    eggNOGiKOG2756 Eukaryota
    ENOG410XP85 LUCA
    GeneTreeiENSGT00390000014242
    HOVERGENiHBG079625
    InParanoidiO95551
    KOiK19619
    OMAiTGNEEGY
    OrthoDBiEOG091G0FBI
    PhylomeDBiO95551
    TreeFamiTF314813

    Family and domain databases

    Gene3Di3.60.10.10, 1 hit
    InterProiView protein in InterPro
    IPR036691 Endo/exonu/phosph_ase_sf
    IPR005135 Endo/exonuclease/phosphatase
    IPR009060 UBA-like_sf
    PfamiView protein in Pfam
    PF03372 Exo_endo_phos, 1 hit
    SUPFAMiSSF46934 SSF46934, 1 hit
    SSF56219 SSF56219, 1 hit

    Sequences (3+)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All

    Isoform 1 (identifier: O95551-1) [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
    MELGSCLEGG REAAEEEGEP EVKKRRLLCV EFASVASCDA AVAQCFLAEN
    60 70 80 90 100
    DWEMERALNS YFEPPVEESA LERRPETISE PKTYVDLTNE ETTDSTTSKI
    110 120 130 140 150
    SPSEDTQQEN GSMFSLITWN IDGLDLNNLS ERARGVCSYL ALYSPDVIFL
    160 170 180 190 200
    QEVIPPYYSY LKKRSSNYEI ITGHEEGYFT AIMLKKSRVK LKSQEIIPFP
    210 220 230 240 250
    STKMMRNLLC VHVNVSGNEL CLMTSHLEST RGHAAERMNQ LKMVLKKMQE
    260 270 280 290 300
    APESATVIFA GDTNLRDREV TRCGGLPNNI VDVWEFLGKP KHCQYTWDTQ
    310 320 330 340 350
    MNSNLGITAA CKLRFDRIFF RAAAEEGHII PRSLDLLGLE KLDCGRFPSD
    360
    HWGLLCNLDI IL
    Length:362
    Mass (Da):40,930
    Last modified:May 1, 1999 - v1
    Checksum:i37892E125DB64410
    GO
    Isoform 2 (identifier: O95551-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-1: M → MRERHDTGACAEPRVGLLFRLKGRCRGGRKM

    Note: No experimental confirmation available.
    Show »
    Length:392
    Mass (Da):44,339
    Checksum:i6B822134BDD395F3
    GO
    Isoform 3 (identifier: O95551-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         60-137: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:284
    Mass (Da):32,176
    Checksum:i3FBF514CDDECB196
    GO

    Computationally mapped potential isoform sequencesi

    There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    X6R5A3X6R5A3_HUMAN
    TRAF and TNF receptor associated pr...
    TDP2 TTRAP, hCG_37519
    304Annotation score:

    Sequence cautioni

    The sequence BAG59230 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti31E → R in AAF64144 (PubMed:10931946).Curated1
    Sequence conflicti61Y → C in BAA92119 (PubMed:14702039).Curated1
    Sequence conflicti72E → G in BAG60857 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_051464166S → G. Corresponds to variant dbSNP:rs35977478Ensembl.1
    Natural variantiVAR_022634249Q → E1 PublicationCorresponds to variant dbSNP:rs2294689Ensembl.1
    Natural variantiVAR_022635268R → Q1 PublicationCorresponds to variant dbSNP:rs17249952Ensembl.1
    Natural variantiVAR_076867307I → V1 PublicationCorresponds to variant dbSNP:rs77273535Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0385231M → MRERHDTGACAEPRVGLLFR LKGRCRGGRKM in isoform 2. 1 Publication1
    Alternative sequenceiVSP_03852460 – 137Missing in isoform 3. 1 PublicationAdd BLAST78

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ269473 mRNA Translation: CAB92966.1
    AF201687 mRNA Translation: AAG35600.1
    AF223469 mRNA Translation: AAF64144.1
    AK002168 mRNA Translation: BAA92119.1
    AK296623 mRNA Translation: BAG59230.1 Different initiation.
    AK298699 mRNA Translation: BAG60857.1
    AY613922 Genomic DNA Translation: AAT09764.1
    AL031775 Genomic DNA No translation available.
    BC017553 mRNA Translation: AAH17553.1
    BC110375 mRNA Translation: AAI10376.1
    CCDSiCCDS4557.1 [O95551-1]
    RefSeqiNP_057698.2, NM_016614.2 [O95551-1]
    UniGeneiHs.403010

    Genome annotation databases

    EnsembliENST00000378198; ENSP00000367440; ENSG00000111802 [O95551-1]
    GeneIDi51567
    KEGGihsa:51567
    UCSCiuc003nej.4 human [O95551-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Cross-referencesi

    Web resourcesi

    SeattleSNPs

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ269473 mRNA Translation: CAB92966.1
    AF201687 mRNA Translation: AAG35600.1
    AF223469 mRNA Translation: AAF64144.1
    AK002168 mRNA Translation: BAA92119.1
    AK296623 mRNA Translation: BAG59230.1 Different initiation.
    AK298699 mRNA Translation: BAG60857.1
    AY613922 Genomic DNA Translation: AAT09764.1
    AL031775 Genomic DNA No translation available.
    BC017553 mRNA Translation: AAH17553.1
    BC110375 mRNA Translation: AAI10376.1
    CCDSiCCDS4557.1 [O95551-1]
    RefSeqiNP_057698.2, NM_016614.2 [O95551-1]
    UniGeneiHs.403010

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5INOX-ray3.21A/B108-362[»]
    5J3PX-ray3.10A/B113-362[»]
    5J3SX-ray3.40A113-362[»]
    ProteinModelPortaliO95551
    SMRiO95551
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi119615, 39 interactors
    IntActiO95551, 26 interactors
    MINTiO95551
    STRINGi9606.ENSP00000367440

    Chemistry databases

    BindingDBiO95551
    ChEMBLiCHEMBL2169736

    PTM databases

    iPTMnetiO95551
    PhosphoSitePlusiO95551

    Polymorphism and mutation databases

    BioMutaiTDP2

    Proteomic databases

    EPDiO95551
    MaxQBiO95551
    PaxDbiO95551
    PeptideAtlasiO95551
    PRIDEiO95551
    ProteomicsDBi50937
    50938 [O95551-2]
    50939 [O95551-3]

    Protocols and materials databases

    DNASUi51567
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000378198; ENSP00000367440; ENSG00000111802 [O95551-1]
    GeneIDi51567
    KEGGihsa:51567
    UCSCiuc003nej.4 human [O95551-1]

    Organism-specific databases

    CTDi51567
    DisGeNETi51567
    EuPathDBiHostDB:ENSG00000111802.13
    GeneCardsiTDP2
    HGNCiHGNC:17768 TDP2
    HPAiCAB073398
    HPA074011
    MalaCardsiTDP2
    MIMi605764 gene
    616949 phenotype
    neXtProtiNX_O95551
    OpenTargetsiENSG00000111802
    Orphaneti404493 Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency
    PharmGKBiPA165618310
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2756 Eukaryota
    ENOG410XP85 LUCA
    GeneTreeiENSGT00390000014242
    HOVERGENiHBG079625
    InParanoidiO95551
    KOiK19619
    OMAiTGNEEGY
    OrthoDBiEOG091G0FBI
    PhylomeDBiO95551
    TreeFamiTF314813

    Enzyme and pathway databases

    ReactomeiR-HSA-5693571 Nonhomologous End-Joining (NHEJ)

    Miscellaneous databases

    ChiTaRSiTDP2 human
    GeneWikiiTTRAP
    GenomeRNAii51567
    PROiPR:O95551
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000111802 Expressed in 236 organ(s), highest expression level in colonic mucosa
    CleanExiHS_TTRAP
    ExpressionAtlasiO95551 baseline and differential
    GenevisibleiO95551 HS

    Family and domain databases

    Gene3Di3.60.10.10, 1 hit
    InterProiView protein in InterPro
    IPR036691 Endo/exonu/phosph_ase_sf
    IPR005135 Endo/exonuclease/phosphatase
    IPR009060 UBA-like_sf
    PfamiView protein in Pfam
    PF03372 Exo_endo_phos, 1 hit
    SUPFAMiSSF46934 SSF46934, 1 hit
    SSF56219 SSF56219, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiTYDP2_HUMAN
    AccessioniPrimary (citable) accession number: O95551
    Secondary accession number(s): B4DKL8
    , B4DQ95, Q2TBE2, Q5JYM0, Q7Z6U5, Q9NUK5, Q9NYY9
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 7, 2005
    Last sequence update: May 1, 1999
    Last modified: November 7, 2018
    This is version 151 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. SIMILARITY comments
      Index of protein domains and families
    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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
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