|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Structure of the glycosylase domain of MBD4== | | ==Structure of the glycosylase domain of MBD4== |
| - | <StructureSection load='4e9e' size='340' side='right' caption='[[4e9e]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4e9e' size='340' side='right'caption='[[4e9e]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4e9e]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E9E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4E9E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4e9e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4E9E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E9E FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3iho|3iho]], [[4e9f|4e9f]], [[4e9g|4e9g]], [[4e9h|4e9h]], [[4ea4|4ea4]], [[4eab|4eab]]</td></tr> | + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4e9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e9e OCA], [https://pdbe.org/4e9e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e9e RCSB], [https://www.ebi.ac.uk/pdbsum/4e9e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e9e ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MBD4, MED1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4e9e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e9e OCA], [http://pdbe.org/4e9e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4e9e RCSB], [http://www.ebi.ac.uk/pdbsum/4e9e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4e9e ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MBD4_HUMAN MBD4_HUMAN]] Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.<ref>PMID:10097147</ref> <ref>PMID:10930409</ref> | + | [[https://www.uniprot.org/uniprot/MBD4_HUMAN MBD4_HUMAN]] Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.<ref>PMID:10097147</ref> <ref>PMID:10930409</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 21: |
Line 19: |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Methyl CpG binding protein|Methyl CpG binding protein]] | + | *[[Methyl CpG binding protein 3D structures|Methyl CpG binding protein 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Morera, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Vigouroux, A]] | + | [[Category: Morera S]] |
| - | [[Category: Hhh dna glycosylase superfamily]] | + | [[Category: Vigouroux A]] |
| - | [[Category: Hydrolase]]
| + | |
| Structural highlights
Function
[MBD4_HUMAN] Mismatch-specific DNA N-glycosylase involved in DNA repair. Has thymine glycosylase activity and is specific for G:T mismatches within methylated and unmethylated CpG sites. Can also remove uracil or 5-fluorouracil in G:U mismatches. Has no lyase activity. Was first identified as methyl-CpG-binding protein.[1] [2]
Publication Abstract from PubMed
Active DNA demethylation in mammals occurs via hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation family of proteins (TETs). 5hmC residues in DNA can be further oxidized by TETs to 5-carboxylcytosines and/or deaminated by the Activation Induced Deaminase/Apolipoprotein B mRNA-editing enzyme complex family proteins to 5-hydromethyluracil (5hmU). Excision and replacement of these intermediates is initiated by DNA glycosylases such as thymine-DNA glycosylase (TDG), methyl-binding domain protein 4 (MBD4) and single-strand specific monofunctional uracil-DNA glycosylase 1 in the base excision repair pathway. Here, we report detailed biochemical and structural characterization of human MBD4 which contains mismatch-specific TDG activity. Full-length as well as catalytic domain (residues 426-580) of human MBD4 (MBD4(cat)) can remove 5hmU when opposite to G with good efficiency. Here, we also report six crystal structures of human MBD4(cat): an unliganded form and five binary complexes with duplex DNA containing a T*G, 5hmU*G or AP*G (apurinic/apyrimidinic) mismatch at the target base pair. These structures reveal that MBD4(cat) uses a base flipping mechanism to specifically recognize thymine and 5hmU. The recognition mechanism of flipped-out 5hmU bases in MBD4(cat) active site supports the potential role of MBD4, together with TDG, in maintenance of genome stability and active DNA demethylation in mammals.
Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA.,Morera S, Grin I, Vigouroux A, Couve S, Henriot V, Saparbaev M, Ishchenko AA Nucleic Acids Res. 2012 Jul 30. PMID:22848106[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bellacosa A, Cicchillitti L, Schepis F, Riccio A, Yeung AT, Matsumoto Y, Golemis EA, Genuardi M, Neri G. MED1, a novel human methyl-CpG-binding endonuclease, interacts with DNA mismatch repair protein MLH1. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3969-74. PMID:10097147
- ↑ Petronzelli F, Riccio A, Markham GD, Seeholzer SH, Stoerker J, Genuardi M, Yeung AT, Matsumoto Y, Bellacosa A. Biphasic kinetics of the human DNA repair protein MED1 (MBD4), a mismatch-specific DNA N-glycosylase. J Biol Chem. 2000 Oct 20;275(42):32422-9. PMID:10930409 doi:10.1074/jbc.M004535200
- ↑ Morera S, Grin I, Vigouroux A, Couve S, Henriot V, Saparbaev M, Ishchenko AA. Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA. Nucleic Acids Res. 2012 Jul 30. PMID:22848106 doi:10.1093/nar/gks714
|
