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Protein

Tyrosyl-DNA phosphodiesterase 2

Gene

TDP2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

    • 5'-tyrosyl-DNA phosphodiesterase activity Source: UniProtKB
    • magnesium ion binding Source: UniProtKB
    • manganese ion binding Source: UniProtKB
    • nuclease activity Source: UniProtKB-KW
    • single-stranded DNA binding Source: UniProtKB
    • transcription corepressor activity Source: ProtInc
    • tyrosyl-RNA phosphodiesterase activity Source: UniProtKB

    GO - Biological processi

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

    Keywords - Molecular functioni

    Hydrolase, Nuclease

    Keywords - Biological processi

    DNA damage, DNA repair

    Keywords - Ligandi

    Magnesium, Metal-binding

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000111802-MONOMER.
    ZFISH:ENSG00000114126-MONOMER.
    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

    HGNCiHGNC:17768. TDP2.

    Subcellular locationi

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • intercellular bridge Source: HPA
    • nucleolus Source: UniProtKB-SubCell
    • nucleus Source: UniProtKB
    • PML body Source: UniProtKB
    Complete GO annotation...

    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
    Modified residuei88Phosphothreonine; by ACVR1B1 Publication1
    Modified residuei92Phosphothreonine; by ACVR1B1 Publication1
    Modified residuei95PhosphoserineCombined sources1

    Post-translational modificationi

    Ubiquitinated by TRAF6.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiO95551.
    MaxQBiO95551.
    PaxDbiO95551.
    PeptideAtlasiO95551.
    PRIDEiO95551.

    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.
    CleanExiHS_TTRAP.
    ExpressionAtlasiO95551. baseline and differential.
    GenevisibleiO95551. HS.

    Organism-specific databases

    HPAiCAB073398.
    HPA054272.

    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. 35 interactors.
    IntActiO95551. 23 interactors.
    MINTiMINT-5005899.
    STRINGi9606.ENSP00000367440.

    Chemistry databases

    BindingDBiO95551.

    Structurei

    Secondary structure

    1362
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi113 – 120Combined sources8
    Helixi129 – 143Combined sources15
    Beta strandi146 – 153Combined sources8
    Helixi155 – 164Combined sources10
    Beta strandi167 – 173Combined sources7
    Beta strandi175 – 177Combined sources3
    Beta strandi179 – 185Combined sources7
    Turni186 – 188Combined sources3
    Beta strandi189 – 198Combined sources10
    Beta strandi203 – 205Combined sources3
    Beta strandi207 – 215Combined sources9
    Beta strandi218 – 224Combined sources7
    Helixi231 – 233Combined sources3
    Helixi234 – 249Combined sources16
    Beta strandi255 – 262Combined sources8
    Helixi269 – 272Combined sources4
    Helixi283 – 286Combined sources4
    Beta strandi291 – 294Combined sources4
    Beta strandi296 – 298Combined sources3
    Turni299 – 301Combined sources3
    Beta strandi316 – 321Combined sources6
    Beta strandi329 – 337Combined sources9
    Beta strandi353 – 360Combined sources8

    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...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the CCR4/nocturin family.Curated

    Phylogenomic databases

    eggNOGiKOG2756. Eukaryota.
    ENOG410XP85. LUCA.
    GeneTreeiENSGT00390000014242.
    HOVERGENiHBG079625.
    InParanoidiO95551.
    KOiK19619.
    OMAiQCFLAEN.
    OrthoDBiEOG091G0FBI.
    PhylomeDBiO95551.
    TreeFamiTF314813.

    Family and domain databases

    Gene3Di3.60.10.10. 1 hit.
    InterProiIPR005135. Endo/exonuclease/phosphatase.
    IPR009060. UBA-like.
    [Graphical view]
    PfamiPF03372. Exo_endo_phos. 1 hit.
    [Graphical view]
    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

    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

    Sequence cautioni

    The sequence BAG59230 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence CAD92510 differs from that shown. Reason: Erroneous gene model prediction.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 rs35977478dbSNPEnsembl.1
    Natural variantiVAR_022634249Q → E.1 PublicationCorresponds to variant rs2294689dbSNPEnsembl.1
    Natural variantiVAR_022635268R → Q.1 PublicationCorresponds to variant rs17249952dbSNPEnsembl.1
    Natural variantiVAR_076867307I → V.1 PublicationCorresponds to variant rs77273535dbSNPEnsembl.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. Translation: CAA21141.1.
    AL031775 Genomic DNA. Translation: CAD92510.1. Sequence problems.
    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

    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. Translation: CAA21141.1.
    AL031775 Genomic DNA. Translation: CAD92510.1. Sequence problems.
    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. 35 interactors.
    IntActiO95551. 23 interactors.
    MINTiMINT-5005899.
    STRINGi9606.ENSP00000367440.

    Chemistry databases

    BindingDBiO95551.
    ChEMBLiCHEMBL2169736.

    PTM databases

    iPTMnetiO95551.
    PhosphoSitePlusiO95551.

    Polymorphism and mutation databases

    BioMutaiTDP2.

    Proteomic databases

    EPDiO95551.
    MaxQBiO95551.
    PaxDbiO95551.
    PeptideAtlasiO95551.
    PRIDEiO95551.

    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.
    GeneCardsiTDP2.
    HGNCiHGNC:17768. TDP2.
    HPAiCAB073398.
    HPA054272.
    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.
    OMAiQCFLAEN.
    OrthoDBiEOG091G0FBI.
    PhylomeDBiO95551.
    TreeFamiTF314813.

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000111802-MONOMER.
    ZFISH:ENSG00000114126-MONOMER.
    ReactomeiR-HSA-5693571. Nonhomologous End-Joining (NHEJ).

    Miscellaneous databases

    ChiTaRSiTDP2. human.
    GeneWikiiTTRAP.
    GenomeRNAii51567.
    PROiO95551.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000111802.
    CleanExiHS_TTRAP.
    ExpressionAtlasiO95551. baseline and differential.
    GenevisibleiO95551. HS.

    Family and domain databases

    Gene3Di3.60.10.10. 1 hit.
    InterProiIPR005135. Endo/exonuclease/phosphatase.
    IPR009060. UBA-like.
    [Graphical view]
    PfamiPF03372. Exo_endo_phos. 1 hit.
    [Graphical view]
    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 historyi
    Integrated into UniProtKB/Swiss-Prot: June 7, 2005
    Last sequence update: May 1, 1999
    Last modified: November 30, 2016
    This is version 139 of the entry and version 1 of the sequence. [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 6
      Human chromosome 6: 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.