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Tyrosyl-DNA phosphodiesterase 2 (Tyr-DNA phosphodiesterase 2) (hTDP2) (EC 3.1.4.-) (5'-tyrosyl-DNA phosphodiesterase) (5'-Tyr-DNA phosphodiesterase) (ETS1-associated protein 2) (ETS1-associated protein II) (EAPII) (TRAF and TNF receptor-associated protein) (Tyrosyl-RNA phosphodiesterase) (VPg unlinkase)

 TYDP2_HUMAN             Reviewed;         362 AA.
O95551; B4DKL8; B4DQ95; Q2TBE2; Q5JYM0; Q7Z6U5; Q9NUK5; Q9NYY9;
07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
01-MAY-1999, sequence version 1.
27-SEP-2017, entry version 143.
RecName: Full=Tyrosyl-DNA phosphodiesterase 2;
Short=Tyr-DNA phosphodiesterase 2;
Short=hTDP2;
EC=3.1.4.-;
AltName: Full=5'-tyrosyl-DNA phosphodiesterase;
Short=5'-Tyr-DNA phosphodiesterase;
AltName: Full=ETS1-associated protein 2;
AltName: Full=ETS1-associated protein II;
Short=EAPII;
AltName: Full=TRAF and TNF receptor-associated protein;
AltName: Full=Tyrosyl-RNA phosphodiesterase;
AltName: Full=VPg unlinkase;
Name=TDP2; Synonyms=EAP2, TTRAP; ORFNames=AD-022;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH TNFRSF5;
TNFRSF8; TNFRSF1B; TRAF2; TRAF3; TRAF5 AND TRAF6, AND TISSUE
SPECIFICITY.
TISSUE=Umbilical vein;
PubMed=10764746; DOI=10.1074/jbc.M000531200;
Pype S., Declercq W., Ibrahimi A., Michiels C.,
Van Rietschoten J.G.I., Dewulf N., de Boer M., Vandenabeele P.,
Huylebroeck D., Remacle J.E.;
"TTRAP, a novel protein that associates with CD40, tumor necrosis
factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs),
and that inhibits nuclear factor-kappa B activation.";
J. Biol. Chem. 275:18586-18593(2000).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH ETS1; ETS2
AND FLI1, AND SUBCELLULAR LOCATION.
PubMed=12743594; DOI=10.1038/sj.onc.1206374;
Pei H., Yordy J.S., Leng Q., Zhao Q., Watson D.K., Li R.;
"EAPII interacts with ETS1 and modulates its transcriptional
function.";
Oncogene 22:2699-2709(2003).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Adrenal gland;
PubMed=10931946; DOI=10.1073/pnas.160270997;
Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
"Gene expression profiling in the human hypothalamus-pituitary-adrenal
axis and full-length cDNA cloning.";
Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 23-362 (ISOFORM 3).
TISSUE=Colon, and Placenta;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[5]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLU-249 AND GLN-268.
SeattleSNPs variation discovery resource;
Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases.
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=14574404; DOI=10.1038/nature02055;
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
"The DNA sequence and analysis of human chromosome 6.";
Nature 425:805-811(2003).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
TISSUE=Duodenum, and Skin;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[8]
INTERACTION WITH ACVR1B AND SMAD3, PHOSPHORYLATION AT THR-88 AND
THR-92, AND MUTAGENESIS OF THR-88 AND THR-92.
PubMed=18039968; DOI=10.1242/dev.000026;
Esguerra C.V., Nelles L., Vermeire L., Ibrahimi A., Crawford A.D.,
Derua R., Janssens E., Waelkens E., Carmeliet P., Collen D.,
Huylebroeck D.;
"Ttrap is an essential modulator of Smad3-dependent Nodal signaling
during zebrafish gastrulation and left-right axis determination.";
Development 134:4381-4393(2007).
[9]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=19413330; DOI=10.1021/ac9004309;
Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
Mohammed S.;
"Lys-N and trypsin cover complementary parts of the phosphoproteome in
a refined SCX-based approach.";
Anal. Chem. 81:4493-4501(2009).
[10]
FUNCTION AS TYROSYL-DNA PHOSPHODIESTERASE, CATALYTIC ACTIVITY,
SUBCELLULAR LOCATION, COFACTOR, AND MUTAGENESIS OF GLU-152 AND
ASP-262.
PubMed=19794497; DOI=10.1038/nature08444;
Ledesma F.C., El Khamisy S.F., Zuma M.C., Osborn K., Caldecott K.W.;
"A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase-
mediated DNA damage.";
Nature 461:674-678(2009).
[11]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[12]
FUNCTION.
PubMed=21030584; DOI=10.1074/jbc.M110.181016;
Zeng Z., Cortes-Ledesma F., El Khamisy S.F., Caldecott K.W.;
"TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in
vertebrate cells and is critical for cellular resistance to
topoisomerase II-induced DNA damage.";
J. Biol. Chem. 286:403-409(2011).
[13]
FUNCTION, AND UBIQUITINATION.
PubMed=21980489; DOI=10.1371/journal.pone.0025548;
Varady G., Sarkadi B., Fatyol K.;
"TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-beta
signaling pathway.";
PLoS ONE 6:E25548-E25548(2011).
[14]
FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR.
PubMed=22405347; DOI=10.1186/1756-0500-5-134;
Adhikari S., Karmahapatra S.K., Karve T.M., Bandyopadhyay S.,
Woodrick J., Manthena P.V., Glasgow E., Byers S., Saha T., Uren A.;
"Characterization of magnesium requirement of human 5'-tyrosyl DNA
phosphodiesterase mediated reaction.";
BMC Res. Notes 5:134-134(2012).
[15]
FUNCTION, AND SUBCELLULAR LOCATION.
PubMed=21921940; DOI=10.1038/cdd.2011.118;
Vilotti S., Biagioli M., Foti R., Dal Ferro M., Lavina Z.S.,
Collavin L., Del Sal G., Zucchelli S., Gustincich S.;
"The PML nuclear bodies-associated protein TTRAP regulates ribosome
biogenesis in nucleolar cavities upon proteasome inhibition.";
Cell Death Differ. 19:488-500(2012).
[16]
FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES,
AND MUTAGENESIS OF ASN-120; GLU-152; ASP-262 AND HIS-351.
PubMed=22822062; DOI=10.1074/jbc.M112.393983;
Gao R., Huang S.Y., Marchand C., Pommier Y.;
"Biochemical characterization of human Tyrosyl DNA Phosphodiesterase 2
(TDP2/TTRAP): a Mg2+/Mn2+-dependent phosphodiesterase specific for the
repair of topoisomerase cleavage complexes.";
J. Biol. Chem. 287:30842-30852(2012).
[17]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22223895; DOI=10.1074/mcp.M111.015131;
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C.,
Meinnel T., Giglione C.;
"Comparative large-scale characterisation of plant vs. mammal proteins
reveals similar and idiosyncratic N-alpha acetylation features.";
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
[18]
ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=22814378; DOI=10.1073/pnas.1210303109;
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
Aldabe R.;
"N-terminal acetylome analyses and functional insights of the N-
terminal acetyltransferase NatB.";
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
[19]
FUNCTION AS TYROSYL-RNA PHOSPHODIESTERASE (MICROBIAL INFECTION), AND
SUBCELLULAR LOCATION (MICROBIAL INFECTION).
PubMed=22908287; DOI=10.1073/pnas.1208096109;
Virgen-Slane R., Rozovics J.M., Fitzgerald K.D., Ngo T., Chou W.,
van der Heden van Noort G.J., Filippov D.V., Gershon P.D.,
Semler B.L.;
"An RNA virus hijacks an incognito function of a DNA repair enzyme.";
Proc. Natl. Acad. Sci. U.S.A. 109:14634-14639(2012).
[20]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-95, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[21]
FUNCTION, TISSUE SPECIFICITY, INVOLVEMENT IN SCAR23, AND VARIANT
VAL-307.
PubMed=24658003; DOI=10.1038/ng.2929;
Gomez-Herreros F., Schuurs-Hoeijmakers J.H., McCormack M.,
Greally M.T., Rulten S., Romero-Granados R., Counihan T.J., Chaila E.,
Conroy J., Ennis S., Delanty N., Cortes-Ledesma F., de Brouwer A.P.,
Cavalleri G.L., El-Khamisy S.F., de Vries B.B., Caldecott K.W.;
"TDP2 protects transcription from abortive topoisomerase activity and
is required for normal neural function.";
Nat. Genet. 46:516-521(2014).
[22]
SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-23 AND LYS-82, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=28112733; DOI=10.1038/nsmb.3366;
Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
Nielsen M.L.;
"Site-specific mapping of the human SUMO proteome reveals co-
modification with phosphorylation.";
Nat. Struct. Mol. Biol. 24:325-336(2017).
-!- FUNCTION: 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.
{ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21030584,
ECO:0000269|PubMed:21921940, ECO:0000269|PubMed:21980489,
ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062,
ECO:0000269|PubMed:24658003}.
-!- FUNCTION: (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.
{ECO:0000269|PubMed:22908287}.
-!- COFACTOR:
Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Evidence={ECO:0000269|PubMed:19794497,
ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062};
Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
Evidence={ECO:0000269|PubMed:19794497,
ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062};
Note=Magnesium. Can use other divalent cations as cofactor in
vitro, such as manganese. {ECO:0000269|PubMed:19794497,
ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062};
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=8 uM for single-stranded 5'-tyrosyl DNA
{ECO:0000269|PubMed:22822062};
Note=kcat is 3 sec(-1) with single-stranded 5'-tyrosyl DNA as
substrate.;
-!- SUBUNIT: Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30,
TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and
ACVR1B/ALK4. {ECO:0000269|PubMed:10764746,
ECO:0000269|PubMed:12743594, ECO:0000269|PubMed:18039968}.
-!- SUBCELLULAR LOCATION: Nucleus. Nucleus, PML body. Nucleus,
nucleolus. Cytoplasm. Note=Localizes to nucleolar cavities
following stress; localization to nucleolus is dependent on PML
protein.
-!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22908287}.
Note=(Microbial infection) In case of infection by picornavirus,
relocalizes to cytoplasmic sites distinct from those containing
viral proteins associated with RNA replication or encapsidation.
{ECO:0000269|PubMed:22908287}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=O95551-1; Sequence=Displayed;
Name=2;
IsoId=O95551-2; Sequence=VSP_038523;
Note=No experimental confirmation available.;
Name=3;
IsoId=O95551-3; Sequence=VSP_038524;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: 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). {ECO:0000269|PubMed:10764746,
ECO:0000269|PubMed:24658003}.
-!- PTM: Ubiquitinated by TRAF6. {ECO:0000269|PubMed:21980489}.
-!- DISEASE: Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23)
[MIM:616949]: A 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.
{ECO:0000269|PubMed:24658003}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the CCR4/nocturin family. {ECO:0000305}.
-!- SEQUENCE CAUTION:
Sequence=BAG59230.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
Sequence=CAD92510.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
-!- WEB RESOURCE: Name=SeattleSNPs;
URL="http://pga.gs.washington.edu/data/ttrap/";
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EMBL; AJ269473; CAB92966.1; -; mRNA.
EMBL; AF201687; AAG35600.1; -; mRNA.
EMBL; AF223469; AAF64144.1; -; mRNA.
EMBL; AK002168; BAA92119.1; -; mRNA.
EMBL; AK296623; BAG59230.1; ALT_INIT; mRNA.
EMBL; AK298699; BAG60857.1; -; mRNA.
EMBL; AY613922; AAT09764.1; -; Genomic_DNA.
EMBL; AL031775; CAA21141.1; -; Genomic_DNA.
EMBL; AL031775; CAD92510.1; ALT_SEQ; Genomic_DNA.
EMBL; BC017553; AAH17553.1; -; mRNA.
EMBL; BC110375; AAI10376.1; -; mRNA.
CCDS; CCDS4557.1; -. [O95551-1]
RefSeq; NP_057698.2; NM_016614.2. [O95551-1]
UniGene; Hs.403010; -.
PDB; 5INO; X-ray; 3.21 A; A/B=108-362.
PDB; 5J3P; X-ray; 3.10 A; A/B=113-362.
PDB; 5J3S; X-ray; 3.40 A; A=113-362.
PDBsum; 5INO; -.
PDBsum; 5J3P; -.
PDBsum; 5J3S; -.
ProteinModelPortal; O95551; -.
SMR; O95551; -.
BioGrid; 119615; 38.
IntAct; O95551; 23.
MINT; MINT-5005899; -.
STRING; 9606.ENSP00000367440; -.
BindingDB; O95551; -.
ChEMBL; CHEMBL2169736; -.
iPTMnet; O95551; -.
PhosphoSitePlus; O95551; -.
BioMuta; TDP2; -.
EPD; O95551; -.
MaxQB; O95551; -.
PaxDb; O95551; -.
PeptideAtlas; O95551; -.
PRIDE; O95551; -.
DNASU; 51567; -.
Ensembl; ENST00000378198; ENSP00000367440; ENSG00000111802. [O95551-1]
GeneID; 51567; -.
KEGG; hsa:51567; -.
UCSC; uc003nej.4; human. [O95551-1]
CTD; 51567; -.
DisGeNET; 51567; -.
EuPathDB; HostDB:ENSG00000111802.13; -.
GeneCards; TDP2; -.
HGNC; HGNC:17768; TDP2.
HPA; CAB073398; -.
HPA; HPA074011; -.
MalaCards; TDP2; -.
MIM; 605764; gene.
MIM; 616949; phenotype.
neXtProt; NX_O95551; -.
OpenTargets; ENSG00000111802; -.
Orphanet; 404493; Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
PharmGKB; PA165618310; -.
eggNOG; KOG2756; Eukaryota.
eggNOG; ENOG410XP85; LUCA.
GeneTree; ENSGT00390000014242; -.
HOVERGEN; HBG079625; -.
InParanoid; O95551; -.
KO; K19619; -.
OMA; QCFLAEN; -.
OrthoDB; EOG091G0FBI; -.
PhylomeDB; O95551; -.
TreeFam; TF314813; -.
Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ).
ChiTaRS; TDP2; human.
GeneWiki; TTRAP; -.
GenomeRNAi; 51567; -.
PRO; PR:O95551; -.
Proteomes; UP000005640; Chromosome 6.
Bgee; ENSG00000111802; -.
CleanEx; HS_TTRAP; -.
ExpressionAtlas; O95551; baseline and differential.
Genevisible; O95551; HS.
GO; GO:0016235; C:aggresome; IDA:HPA.
GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
GO; GO:0016604; C:nuclear body; IDA:HPA.
GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0016605; C:PML body; IDA:UniProtKB.
GO; GO:0070260; F:5'-tyrosyl-DNA phosphodiesterase activity; IDA:UniProtKB.
GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB.
GO; GO:0004518; F:nuclease activity; IEA:UniProtKB-KW.
GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB.
GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc.
GO; GO:0036317; F:tyrosyl-RNA phosphodiesterase activity; IDA:UniProtKB.
GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc.
GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
GO; GO:0048666; P:neuron development; IMP:UniProtKB.
Gene3D; 3.60.10.10; -; 1.
InterPro; IPR005135; Endo/exonuclease/phosphatase.
InterPro; IPR009060; UBA-like.
Pfam; PF03372; Exo_endo_phos; 1.
SUPFAM; SSF46934; SSF46934; 1.
SUPFAM; SSF56219; SSF56219; 1.
1: Evidence at protein level;
3D-structure; Acetylation; Alternative splicing; Complete proteome;
Cytoplasm; DNA damage; DNA repair; Hydrolase; Isopeptide bond;
Magnesium; Mental retardation; Metal-binding; Neurodegeneration;
Nuclease; Nucleus; Phosphoprotein; Polymorphism; Reference proteome;
Spinocerebellar ataxia; Ubl conjugation.
CHAIN 1 362 Tyrosyl-DNA phosphodiesterase 2.
/FTId=PRO_0000065678.
ACT_SITE 351 351 Proton acceptor. {ECO:0000305}.
METAL 120 120 Magnesium. {ECO:0000305}.
METAL 152 152 Magnesium. {ECO:0000250}.
METAL 262 262 Magnesium. {ECO:0000305}.
METAL 264 264 Magnesium. {ECO:0000250}.
METAL 350 350 Magnesium. {ECO:0000250}.
METAL 351 351 Magnesium. {ECO:0000305}.
MOD_RES 1 1 N-acetylmethionine.
{ECO:0000244|PubMed:19413330,
ECO:0000244|PubMed:22223895,
ECO:0000244|PubMed:22814378}.
MOD_RES 88 88 Phosphothreonine; by ACVR1B.
{ECO:0000269|PubMed:18039968}.
MOD_RES 92 92 Phosphothreonine; by ACVR1B.
{ECO:0000269|PubMed:18039968}.
MOD_RES 95 95 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
CROSSLNK 23 23 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO2).
{ECO:0000244|PubMed:28112733}.
CROSSLNK 82 82 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO2).
{ECO:0000244|PubMed:28112733}.
VAR_SEQ 1 1 M -> MRERHDTGACAEPRVGLLFRLKGRCRGGRKM (in
isoform 2).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_038523.
VAR_SEQ 60 137 Missing (in isoform 3).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_038524.
VARIANT 166 166 S -> G (in dbSNP:rs35977478).
/FTId=VAR_051464.
VARIANT 249 249 Q -> E (in dbSNP:rs2294689).
{ECO:0000269|Ref.5}.
/FTId=VAR_022634.
VARIANT 268 268 R -> Q (in dbSNP:rs17249952).
{ECO:0000269|Ref.5}.
/FTId=VAR_022635.
VARIANT 307 307 I -> V (in dbSNP:rs77273535).
{ECO:0000269|PubMed:24658003}.
/FTId=VAR_076867.
MUTAGEN 88 88 T->A: Abolishes function, but retains
ability to interact with SMAD3; when
associated with A-92.
{ECO:0000269|PubMed:18039968}.
MUTAGEN 92 92 T->A: Abolishes function, but retains
ability to interact with SMAD3; when
associated with A-88.
{ECO:0000269|PubMed:18039968}.
MUTAGEN 120 120 N->A: Strongly reduced phosphodiesterase
activity. {ECO:0000269|PubMed:22822062}.
MUTAGEN 152 152 E->A: Loss of phosphodiesterase activity.
{ECO:0000269|PubMed:19794497,
ECO:0000269|PubMed:22822062}.
MUTAGEN 262 262 D->A: Loss of phosphodiesterase activity.
{ECO:0000269|PubMed:19794497,
ECO:0000269|PubMed:22822062}.
MUTAGEN 351 351 H->A: Loss of phosphodiesterase activity.
{ECO:0000269|PubMed:22822062}.
CONFLICT 31 31 E -> R (in Ref. 3; AAF64144).
{ECO:0000305}.
CONFLICT 61 61 Y -> C (in Ref. 4; BAA92119).
{ECO:0000305}.
CONFLICT 72 72 E -> G (in Ref. 4; BAG60857).
{ECO:0000305}.
STRAND 113 120 {ECO:0000244|PDB:5J3P}.
HELIX 129 143 {ECO:0000244|PDB:5J3P}.
STRAND 146 153 {ECO:0000244|PDB:5J3P}.
HELIX 155 164 {ECO:0000244|PDB:5J3P}.
STRAND 167 173 {ECO:0000244|PDB:5J3P}.
STRAND 175 177 {ECO:0000244|PDB:5J3P}.
STRAND 179 185 {ECO:0000244|PDB:5J3P}.
TURN 186 188 {ECO:0000244|PDB:5J3P}.
STRAND 189 198 {ECO:0000244|PDB:5J3P}.
STRAND 203 205 {ECO:0000244|PDB:5J3S}.
STRAND 207 215 {ECO:0000244|PDB:5J3P}.
STRAND 218 224 {ECO:0000244|PDB:5J3P}.
HELIX 231 233 {ECO:0000244|PDB:5INO}.
HELIX 234 249 {ECO:0000244|PDB:5J3P}.
STRAND 255 262 {ECO:0000244|PDB:5J3P}.
HELIX 269 272 {ECO:0000244|PDB:5J3P}.
HELIX 283 286 {ECO:0000244|PDB:5J3P}.
STRAND 291 294 {ECO:0000244|PDB:5INO}.
STRAND 296 298 {ECO:0000244|PDB:5J3P}.
TURN 299 301 {ECO:0000244|PDB:5J3P}.
STRAND 316 321 {ECO:0000244|PDB:5J3P}.
STRAND 329 337 {ECO:0000244|PDB:5J3P}.
STRAND 353 360 {ECO:0000244|PDB:5J3P}.
SEQUENCE 362 AA; 40930 MW; 37892E125DB64410 CRC64;
MELGSCLEGG REAAEEEGEP EVKKRRLLCV EFASVASCDA AVAQCFLAEN DWEMERALNS
YFEPPVEESA LERRPETISE PKTYVDLTNE ETTDSTTSKI SPSEDTQQEN GSMFSLITWN
IDGLDLNNLS ERARGVCSYL ALYSPDVIFL QEVIPPYYSY LKKRSSNYEI ITGHEEGYFT
AIMLKKSRVK LKSQEIIPFP STKMMRNLLC VHVNVSGNEL CLMTSHLEST RGHAAERMNQ
LKMVLKKMQE APESATVIFA GDTNLRDREV TRCGGLPNNI VDVWEFLGKP KHCQYTWDTQ
MNSNLGITAA CKLRFDRIFF RAAAEEGHII PRSLDLLGLE KLDCGRFPSD HWGLLCNLDI
IL


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