| General information | | DisProt: | DP00719 | | Name: | G/T mismatch-specific thymine DNA glycosylase | | Synonym(s): | TDG_HUMAN
Thymine-DNA glycosylase
TDG
| | First appeared in release: | Release 5.9 (02/23/2012) | | UniProt: | Q13569 | | UniGene: | | | SwissProt: | TDG_HUMAN | | TrEMBL: | | | NCBI (GI): | | | Source organism: | Homo sapiens (Human) | | Sequence length: | 410 | | Percent disordered: | 44% | | Homologues: | |
| Native sequence |
10 20 30 40 50 60
| | | | | |
MEAENAGSYS LQQAQAFYTF PFQQLMAEAP NMAVVNEQQM PEEVPAPAPA QEPVQEAPKG - 60
RKRKPRTTEP KQPVEPKKPV ESKKSGKSAK SKEKQEKITD TFKVKRKVDR FNGVSEAELL - 120
TKTLPDILTF NLDIVIIGIN PGLMAAYKGH HYPGPGNHFW KCLFMSGLSE VQLNHMDDHT - 180
LPGKYGIGFT NMVERTTPGS KDLSSKEFRE GGRILVQKLQ KYQPRIAVFN GKCIYEIFSK - 240
EVFGVKVKNL EFGLQPHKIP DTETLCYVMP SSSARCAQFP RAQDKVHYYI KLKDLRDQLK - 300
GIERNMDVQE VQYTFDLQLA QEDAKKMAVK EEKYDPGYEA AYGGAYGENP CSSEPCGFSS - 360
NGLIESVELR GESAFSGIPN GQWMTQSFTD QIPSFSNHCG TQEQEEESHA
|
| Functional narrative |
Function: In the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. This enzyme corrects G/T mispairs to G/C pairs. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar- phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.
CATALYTIC ACTIVITY: Hydrolyzes mismatched double-stranded DNA and polynucleotides, releasing free thymine. Q9GZX7:AICDA; NbExp=5; IntAct=EBI-348333, EBI-3834328; P24522:GADD45A; NbExp=3; IntAct=EBI-348333, EBI-448167;
Subcellular Location: Nucleus.
PTM: Sumoylation on Lys-330 by either SUMO1 or SUMO2 induces dissociation of the product DNA.
SIMILARITY: Belongs to the TDG/mug DNA glycosylase family.
WEB RESOURCE: Name=NIEHS-SNPs; URL='http://egp.gs.washington.edu/data/tdg/';
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| Map of ordered and disordered regions |
Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.
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| Region 1 | | Type: | Disordered | | Name: | N-terminal | | Location: | 1 - 50 | | Length: | 50 | | Region sequence: |
MEAENAGSYSLQQAQAFYTFPFQQLMAEAPNMAVVNEQQMPEEVPAPAPA | | Modification type: | Native
| | PDB: | | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | | | Functional subclasses: | Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6.6; TDG 2 mM; NaiPO4 (buffer) 100 mM; EDTA (buffer) 0.5 mM; D2O (buffer) 5 %)
| References:
- Smet-Nocca C, Wieruszeski JM, Chaar V, Leroy A, Benecke A. "The thymine-DNA glycosylase regulatory domain: residual structure and DNA binding." Biochemistry. 2008; 47(25): 6519-30. PubMed: 18512959
| Comments:
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| Region 2 | | Type: | Disordered w/ Residual Structure | | Name: | Regulatory Domain (RD) | | Location: | 51 - 111 | | Length: | 61 | | Region sequence: |
QEPVQEAPKGRKRKPRTTEPKQPVEPKKPVESKKSGKSAKSKEKQEKITDTFKVKRKVDR
F | | Modification type: | Native
| | PDB: | | | Structural/functional type: | Function arises via a disorder to order transition
| | Functional classes: | Modification site
Molecular recognition effectors
| | Functional subclasses: | Acetylation
Autoregulatory
Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Transactivation (transcriptional activation)
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6.6; D2O (buffer) 5 %; EDTA (buffer) 0.5 mM; NaiPO4 (buffer) 100 mM; TDG 2 mM)
| References:
- Smet-Nocca C, Wieruszeski JM, Chaar V, Leroy A, Benecke A. "The thymine-DNA glycosylase regulatory domain: residual structure and DNA binding." Biochemistry. 2008; 47(25): 6519-30. PubMed: 18512959
| Comments:Smet-Nocca et al (2008) describe the RD as essential for G:T mismatch repair, among its numerous other functions.
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| Region 3 | | Type: | Ordered | | Name: | Catalytic Domain (CAT) | | Location: | 112 - 339 | | Length: | 228 | | Region sequence: |
NGVSEAELLTKTLPDILTFNLDIVIIGINPGLMAAYKGHHYPGPGNHFWKCLFMSGLSEV
QLNHMDDHTLPGKYGIGFTNMVERTTPGSKDLSSKEFREGGRILVQKLQKYQPRIAVFNG
KCIYEIFSKEVFGVKVKNLEFGLQPHKIPDTETLCYVMPSSSARCAQFPRAQDKVHYYIK
LKDLRDQLKGIERNMDVQEVQYTFDLQLAQEDAKKMAVKEEKYDPGYE | | Modification type: | Complex
| | PDB: | 1WYW:A, 2D07:A, 2RBA:A | | Structural/functional type: | Function arises from the ordered state
| | Functional classes: | Molecular recognition effectors
| | Functional subclasses: | Protein-DNA binding
Protein-protein binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6.6; D2O (buffer) 5 mM; EDTA (buffer) 0.5 mM; NaiPO4 (buffer) 100 mM; TDG 2 mM)
- X-ray crystallography (293 K; pH: 8.5; MgCl2 0.2 ; PEG3350 25 %; TDG-SUMO1 (PDB 1WYW); Tris 0.1 M)
- X-ray crystallography (293 K; pH: 5; sodium malonate 1.5 M; TDG-SUMO3 (PDB 2D07))
- X-ray crystallography (295 K; pH: 7.5; DNA duplex (20% molar excess); DTT 0.5 mM; K/Na tartrate tetrahydrate 0.2 M; NaCl 100 mM; PEG 3350 20 %; TDG (PDB 2RBA) 8 mg/mL; Tris-HCL 10 mM)
| References:
- Baba D, Maita N, Jee JG, Uchimura Y, Saitoh H, Sugasawa K, Hanaoka F, Tochio H, Hiroaki H, Shirakawa M. "Crystal structure of SUMO-3-modified thymine-DNA glycosylase." J. Mol. Biol.. 2006; 359(1): 137-47. PubMed: 16626738
- Baba D, Maita N, Jee JG, Uchimura Y, Saitoh H, Sugasawa K, Hanaoka F, Tochio H, Hiroaki H, Shirakawa M. "Crystal structure of thymine DNA glycosylase conjugated to SUMO-1." Nature. 2005; 435(7044): 979-82. PubMed: 15959518
- Maiti A, Morgan MT, Pozharski E, Drohat AC. "Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition." Proc. Natl. Acad. Sci. U.S.A.. 2008; 105(26): 8890-5. PubMed: 18587051
- Smet-Nocca C, Wieruszeski JM, Chaar V, Leroy A, Benecke A. "The thymine-DNA glycosylase regulatory domain: residual structure and DNA binding." Biochemistry. 2008; 47(25): 6519-30. PubMed: 18512959
| Comments:Crystal structures used TDG fragment in complex (1WYW: SUMO1-conjugated; 2D07: SUMO-3-modified; 2RBA: abasic and undamaged DNA-bound).
NMR from Smet-Nocca et al (2008) using full-length TDG.
Smet-Nocca describe the CAT domain as G:U Glycosylase from aa 112-362 and as G:T Glycosylase from aa ~57-362.
|
| Region 4 | | Type: | Disordered | | Name: | C-terminal domain (CTD) | | Location: | 340 - 410 | | Length: | 71 | | Region sequence: |
AAYGGAYGENPCSSEPCGFSSNGLIESVELRGESAFSGIPNGQWMTQSFTDQIPSFSNHC
GTQEQEEESHA | | Modification type: | Native
| | PDB: | | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | | | Functional subclasses: | Autoregulatory
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6.6; D2O (buffer) 5 mM; EDTA (buffer) 0.5 mM; NaiPO4 (buffer) 100 mM; TDG 2 mM)
| References:
- Fuxreiter M, Simon I, Bondos S. "Dynamic protein-DNA recognition: beyond what can be seen." Trends Biochem. Sci.. 2011; 36(8): 415-23. PubMed: 21620710
- Smet-Nocca C, Wieruszeski JM, Chaar V, Leroy A, Benecke A. "The thymine-DNA glycosylase regulatory domain: residual structure and DNA binding." Biochemistry. 2008; 47(25): 6519-30. PubMed: 18512959
| Comments:A discussion of the dynamic nature of the CTD of TDG in a "fuzzy" protein-DNA complex is found in Fuxreiter et al (2011).
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| Comments |
Verification request sent 2-21-2012 (PMID:18512959)
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